\r\n\tNotably, the book encourages academic scholars and researchers to contribute to the modern concepts of CSR. Fundamentally, it speaks for well-developed literature for entrepreneurs and managers, thus assisting them in the decision-making process. \r\n\tFurthermore, this book is of great value to policymakers, practitioners, and corporations, thus contributing to various disciplines (e.g., social science and management). \r\n\tThese proposed themes encourage future researchers and professionals to share their ideas, concepts and work concerning these subject domains. All these suggested topics had recommended under the rubrics of CSR. Perhaps, all the professionals, researchers, and scholars are welcome to submit their piece of work, in particular to the suggested topics. \r\n\tIndeed, the recommended topics include the following but are not limited to these only. \r\n\t• Corporate Governance and Sustainability \r\n\t• Green Innovation and CSR \r\n\t• Social Entrepreneurship \r\n\t• Green Economy and Social and Environmental Sustainability \r\n\t• Sustainable Development and Industrialization
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1. Introduction
When people are asked why health is important, many are unable to answer it. The reason for this may be due to their lack of awareness of the importance of health and the consequent lack of proper self-care. Health can generally be considered an essential basis of life, but many people still do things that show that health is not a priority in their lives. They spend a lot of time on the opportunities they find but do not spend time learning what is good for them to exercise or stay healthy; they spend their budget on Nonsignificant things. But for a more nutritious diet, they pay less.
According to the World Health Organization’s definition, health is a state of complete physical, mental and social well-being and not only the absence of disease or infirmity. This definition of health has been given more attention since 1978 at the UN Summit in Almaty. Due to the considerable differences in the level of health in different countries of the world, the members of this organization were required to provide Primary Health Care by providing an essential package aimed at reducing the health gap between different countries and with the goal of Health for All by the year 2000. Undoubtedly, one of the most critical concerns and challenges that different countries have faced in providing primary health care to their population has been the lack of resources in the face of the growing need to receive this care during all these years.
So from the perspective of health economists, health is a durable good, or type of capital, that provides services. The flow of services produced from the stock of health capital is consumed continuously over an individual’s lifetime. Each person is assumed to be endowed with a given stock of health at the birth time, such as a year. Over the period, the stock of health depreciates with age and maybe promoted by investments in Health services. Death occurs when an individual’s stock of health falls below a critical minimum level.
2. Demand
To request a product or service, you must ask for it, afford it, and have a specific plan for purchasing it. Desires are, in fact, the unlimited desires and inclinations that people have for goods and services. Imagine being able to afford something if you could afford it or it was not so expensive. When we make choices, scarcity guarantees that many of our desires will never be met. Demand reflects our plan and vision for the demands that will be met. The amount of goods and services that the consumer plans to buy depends on many factors: commodity prices, related commodity prices, personal income, expected future prices, population, advertising, and preferences.
We must first discuss the relationship between the demand for a good or service and the price. All other factors influencing demand must be kept constant to study this relationship called the Citrus Paribus principle. The demand for a good or service is inversely related to its price; as the price increases, the demand for it decreases, and vice versa. Of course, the rate of demand response to price changes is not the same for all goods, which will be discussed in the topic of elasticity [1].
2.1 Demand curve
The demand curve is a geometric location of points where the dependent variable is the rate of use of a good, and the independent variable is the price of that good; in general, the demand curve shows the maximum demand for a good at different prices and also represent the ultimate price for a certain amount of a good. Usually, the price variable is shown on the y axis and the amount of goods or services on the x-axis (Figure 1).
Figure 1.
Demand curve.
This shows the maximum amount someone is willing to pay for a small increment in consumption rate. Care should be taken in using the “demand” to mean the amount of consumption of a particular good or service at a specific price and to use it to mean a range of corresponding values in the price range (for example, one point on the demand curve versus the whole Points on the curve). The demand for a good or service is a function of its relative price and buyers’ income. The demand curve is a two-dimensional representation of this process. Responding to price changes is moving along the demand curve and responding to changes in revenue as the entire demand curve changes and shifts (Figure 2). Some of the characteristics of the demand side that should always be kept in mind when using the demand curve in healthcare, especially when making normative statements about well-being, are: Uncertainty on the part of the consumer about the likelihood of future illness; Side effects, the effectiveness of treatment methods and their possible cost. When sick, people experience anxiety, disability, suffering, and pain that may not be considered in the theory of desirability; It is also important to note that there may be an external demand for care and treatment of a person in addition to their need; And the fact that the price at which the applicant responds to the service or goods may in no way be an accurate reflection of the final cost of providing that product or service to the service provider.
Figure 2.
Change in demand curve.
We can also consider the demand curve as a payment ability curve that measures the ultimate benefit. This curve shows the highest price a person is willing and able to pay for the last unit purchased. If there are fewer goods available, the highest price that a person is willing and able to pay for a larger unit will be high. But as the quantity of available goods increases, the ultimate benefit of each additional unit decreases, and the highest price offered on the demand curve decreases.
In addition to the price of the product in question, which is inversely related to the demand for that product, we can examine the relationship between the demand for a product and other factors in the space of the demand curve.
Prices of other goods: The amount of goods or services that consumers plan to buy depends in part on the prices of other goods and services. In this case, there are two types of goods: substitute goods and complementary goods. Two substitute goods can be used instead of each other, and if the price of one of them increases, the demand for that product will decrease, and people will be more likely to demand a substitute product. For example, if beef and chicken are two substitutes, as the price of beef increases, so makes the demand for chicken.
A complementary good is a good that is used with another commodity, and if the price of one of these commodities increases, in addition to the demand for that commodity, the demand for the other commodity also decreases.
Income: Assuming other factors are constant when people’s incomes increase, they buy more goods and services, and vice versa. Demand increases as income increases are normal goods, and goods for which demand decreases as income increases are called inferior goods. But in general, it can be said that the demand for health goods and services has little to do with income. Because medical goods and services provide their health reserves, and as a result, people’s income cannot have a significant impact on demand for these goods. However, rising incomes will increase the demand for luxury medical services.
Population: Demand also depends on the size and age structure of the population. If the population increases, the demand for all goods and services increases, and the population decrease. The demand for goods and services decreases. At the same time, as other factors remain constant, as the population in a particular age group increases, so makes the demand for goods and services used by that age group.
Consumer’s Preferences: Demand also depends on consumer preferences. Preferences are people’s tastes and attitudes towards different goods and services. Preferences are formed based on previous experiences, genetic factors, propaganda, religious beliefs, and other cultural and social factors [2, 3].
2.2 Medical goods
Medical care consists of countless goods and services that maintain, improve, or restore a person’s health. For example, a young man may have wrist surgery to repair a torn tendon so he can return to work, an older woman may have cataract surgery to improve her vision, or a parent may have to Bring their child to a healthcare center for an annual dental checkup to prevent future problems. Prescription drugs, prescription glasses, and dentures are examples of medical supplies, while surgeries, periodic physical examinations, and visits to medical professionals are examples of medical services. Preventive and medical care are heterogeneous, making it difficult to measure and quantify medical care units accurately. Medical care services have four characteristics that distinguish these from other goods and services: intangibility, inseparability, inventory, and inconsistency.
Intangibility means that the five senses are incapable of evaluating medical services. Unlike new shoes, a vegetable salad dinner, or a new cell phone, the consumer cannot see, taste, or touch medical services. Indivisibility also means that the production and consumption of a medical service take place simultaneously. For example, when you see an ophthalmologist for an examination, you use ophthalmic services right at the time of production. In addition, a patient is often seen as both a producer and a consumer. Inventory is directly related to inseparability. Because the production and consumption of a medical service occur simultaneously, healthcare providers cannot store or maintain medical services. For example, a physiotherapist cannot provide a list of different physiotherapy services to meet demand during busy times. Finally, inconsistency means that the variety, composition, and quality of medical services are very different. Although different people may see a doctor simultaneously, there are various reasons for visiting a doctor. One person may see a doctor because of a typical physical problem, while another may see a doctor because of a heart attack. The combination of prescribed medical care or the frequency of its use can vary significantly from person to person and at different times [4, 5].
Demand for healthcare: Demand requires people to seek a service they can afford and are willing to pay for it. The need for healthcare is the care that doctors believe is essential for a person to stay healthy or healthy. Sometimes, patients think they need healthcare, but doctors believe they cannot benefit from such care. Sometimes the doctor believes that there is a medical need, but the patient does not consult his doctor because he prefers not to receive treatment or that he has not recognized the need. Even if patients have as much knowledge as doctors, their demands may be different from their needs.
The following factors affect the demand for healthcare:
Needs (based on patient perception)
Patient preferences
Price or cost of use
Income
transportation cost
waiting time
Quality of care (based on patient perception)
The use of healthcare depends on demand and availability. If planners allocate resources based on need rather than demand, they may find themselves in a situation where some services are underused, and some services are overused.
Just as the healthcare market is different from other commodities, so is the demand for healthcare different from the simple demand model. One of the differences is that healthcare is not demanded because it is self-satisfying. After all, healthcare itself does not lead to satisfaction. Instead, healthcare is in demand because people are satisfied with their activities when they are healthy. So the demand for healthcare is a derived demand.
Patients’ perceptions of their need and capacity to benefit from healthcare are strongly influenced by physicians and healthcare providers. Although in economics, it is assumed that consumers can make informed decisions about their consumption patterns, healthcare consumers delegate this decision-making power to healthcare workers who are more aware of them. This phenomenon is due to information asymmetry between healthcare providers and patients, which carries the risk of induced demand by providers to increase revenue. Another complication stems from the fact that healthcare is highly heterogeneous. Each patient has a relatively different combination of pain and symptoms. Therefore each patient needs to purchase a fairly different package of care that both the patient and the physician have uncertainty about its effectiveness in meeting the need.
Another critical difference is that many health services are paid for by third parties. Payments by third parties or insurance companies Although they significantly increase people’s purchasing power for healthcare, it is also important to note that they can lead to ethical risks and increase demand for services that patients may not need.
Demand for healthcare depends on the level of consumption of an individual in case of illness; the amount of consumption can differ according to the factors affecting the demand, such as income, service price, education, norms, social traditions, and quality. A person’s decision to use or use services is related to his or her illness/injury status rather than healthcare. Developing countries are focused on promoting healthcare as an essential policy to improve health outcomes and fulfill international obligations and universal coverage of health services. However, many policies have focused more on improving physical access than on the demand-side healthcare needs pattern. In low-income countries, allocating scarce financial resources is based on clear criteria for the impact of investment in the health sector on service demand.
In these countries, due to the lack or weakness of social security systems, the occurrence of the disease leads to increased health costs and reduced labor productivity and leads to a loss of household welfare. In developed countries, due to insurance, many health services are used with minimal consumer participation in the payment; however, in developing countries, concerns about less use of health services, to the extent of supply. Or poor access is associated. However, even in health services, due to various barriers on the demand side, related to the cost of treatment, travel costs, and quality of services, the rate of exploitation is low. Also, the importance of a person’s health status in a clinical context is related to the analysis and social evaluation of a person’s health and social environment. Studies have shown that the risk of death is related to people’s perception of the health importance of maintaining it. Since one of the priorities of health policymakers is to improve people’s health, various factors that directly and indirectly affect the demand for health services should be examined more carefully. Identifying the factors influencing individuals’ decision to request healthcare services and choosing from different providers. Therefore, evaluating the determinants of demand for health services will introduce and implement appropriate incentive schemes to encourage better health services. Because health is one of the essential components of human capital and healthy human beings are the center of sustainable development, health can significantly increase the ability of individuals to perform various activities, including productive activities. As a result, people are looking for health. At the individual level, health is mainly influenced by multiple factors such as biological factors, lifestyle, purchased non-medical services, purchased medical services and goods, and different socio-economic characteristics. People’s understanding and expectation of healthcare quality are essential because the perceived quality of health services often affects health services’ behavior and consumption patterns [6].
2.3 Derived demand for healthcare
Grossman used human capital theory to explain the demand for healthcare. According to human capital theory, people invest in themselves through education and health to increase their income. Grossman proposed an approach in which many important aspects of the demand for health services differ from the traditional demand approach:
That consumers are looking for health and demand health services to achieve it.
To achieve health, consumers buy health services from the market and combine them with their efforts to improve health, such as diet and exercise.
The health gained lasts more than a period and is not immediately depreciated to be analyzed as a capital good.
Most notably, health can be considered as both a consumer good and a capital good. From the people’s point of view, health is a consumer product because it makes them feel better. As a capital good, it is also suitable for people’s health because it increases the number of healthy days of life to work and earn money. Figure 3 provides a simple diagram that explains the concept of health capital. Just as one thinks that cars or laptops are capital goods that use the flow of their services over time, one can also understand the savings of one’s health capital, the outcome of which is “healthy days”. Outflow may be considered as one dimension of healthy days or measured in several dimensions of physical, mental health, and limited activity. People consume a range of health inputs, including healthcare inputs, diet, exercise, and time, so they invest in health savings. These investments help maintain or improve consumers’ health reserves, providing them with healthy days. Over time, health reserves may either grow, remain constant, or decrease with age due to illness or injury. As mentioned in Box 3, many technologies may generate health capital, using different amounts of time or health goods and services. Figure 3 shows how the ultimate goal of “healthy days” guides consumer decisions about the amount, time, and cost of investing in health storage. We will see that the prices of healthcare, the rate of wages of individuals, and their productivity in the production of health determine how resources are allocated between health capital and other goods and services that people buy. Consider a consumer who buys market inputs (e.g., medical care, food, clothing) and combines them with his or her own time to generate a health capital reserve that increases his or her utility [2].
Figure 3.
Investing in health.
2.4 Price elasticity of demand
As an economic principle, the price of a good and the demand for that good are inversely related. That is, the higher the price of a commodity, the less demand there is for that commodity, and the lower the price of a good, the greater the demand for it. Price elasticity of demand shows that a one percent change in a good price causes a few percent changes in the demand. For example, if the price of a car rises by one percent, the demand for it will fall by a few percent, and vice versa, if the price of a vehicle falls by one percent, the demand will increase by a few percent.
Three things can happen when we calculate the price elasticity for a commodity:
When a one percent change in the price of a commodity occurs, the demand for that commodity changes by more than one percent. These types of goods are very price sensitive.
When a one percent change in a good price causes the demand for that good to change by less than one percent, this type of product is called inelastic. Demand for this type of goods shows a mild reaction to price changes.
The third case is when a one percent change in the price of a good causes a one percent change in the demand for that good.
If there is an inverse relationship between price and demand, demand elasticity will always be negative because the percentage change in one face or denominator is a negative fraction. Therefore, after calculating the price elasticity of demand, if the result, regardless of the negative sign of the number, becomes more than one, the commodity with elasticity is less than one, the good without elasticity, and if it is equal to one, the good has a single elasticity.
Although the price elasticity of a commodity can be determined only by collecting price information and calculating, some factors affect this ratio.
2.5 Factors affecting the price elasticity of demand
Alternative goods: The more alternative goods there are, the higher the price elasticity of that product. That is, when the price changes, the demand for that product changes more drastically. Also, price changes in a product cause a shift in the demand for alternative goods. In the healthcare sector, there are usually few alternatives to a health or medical intervention.
Complementary goods: When a product has a supplement, a change in the price of a complementary product causes a change in the demand for another product. Maternal and child care can be mentioned as complementary goods in the field of health (Figure 4).
Figure 4.
Types of elasticity.
Commodity prices: In general, if the price of a commodity is very low, the amount of demand does not react to price changes. But high-priced products are attractive. On the other hand, different results are obtained depending on the price at which the demand elasticity is calculated. As mentioned initially, the price of a product has an inverse relationship with the amount of demand. When the price is precisely in the middle of the demand curve of a commodity, the commodity has a single elasticity. Also, if the price is less than the midpoint, the product in that range is unattractive. If the price is above the midpoint, the product will be pulled. You can see this in the chart below.
Marginal modes in demand elasticity: There are also two cases in which the product is completely elastic or completely non-elastic. If the good is fully elastic, the demand for that good will be zero if there is a slight change in the price of the good. Perhaps this is the case for a salesperson in a highly competitive market. If the good is completely inelastic, demand is a fixed figure, regardless of the price range. You can see these modes in Figure 5.
Figure 5.
Marginal modes in demand elasticity.
\n',keywords:"Healthcare Services, Demand, Demand Curve, Price, Health Economics",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/77622.pdf",chapterXML:"https://mts.intechopen.com/source/xml/77622.xml",downloadPdfUrl:"/chapter/pdf-download/77622",previewPdfUrl:"/chapter/pdf-preview/77622",totalDownloads:445,totalViews:0,totalCrossrefCites:0,totalDimensionsCites:0,totalAltmetricsMentions:0,impactScore:0,impactScorePercentile:43,impactScoreQuartile:2,hasAltmetrics:0,dateSubmitted:"June 3rd 2021",dateReviewed:"June 15th 2021",datePrePublished:"July 20th 2021",datePublished:"February 9th 2022",dateFinished:"July 20th 2021",readingETA:"0",abstract:"Healthy human beings are the center of sustainable development, and human beings have long sought to maintain and improve their health by increasing their health reserves. In general, the use of services or the demand for medical services has a vital role in improving the level of health of each person. The demand for healthcare is a demand derived from the demand for health and is influenced by several factors, including price, income, population, etc.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/77622",risUrl:"/chapter/ris/77622",book:{id:"10705",slug:"healthcare-access"},signatures:"Alireza Ghorbani",authors:[{id:"355041",title:"Associate Prof.",name:"Alireza",middleName:null,surname:"Ghorbani",fullName:"Alireza Ghorbani",slug:"alireza-ghorbani",email:"ghorbania1474@yahoo.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Demand",level:"1"},{id:"sec_2_2",title:"2.1 Demand curve",level:"2"},{id:"sec_3_2",title:"2.2 Medical goods",level:"2"},{id:"sec_4_2",title:"2.3 Derived demand for healthcare",level:"2"},{id:"sec_5_2",title:"2.4 Price elasticity of demand",level:"2"},{id:"sec_6_2",title:"2.5 Factors affecting the price elasticity of demand",level:"2"}],chapterReferences:[{id:"B1",body:'Culyer, A. J. (2008). The Dictionary of Health Economics: Edward Elgar'},{id:"B2",body:'Folland, S., Goodman, A. C., Charles, A., & Stano, M. (2017). The Economics of Health and Health Care: Taylor & Francis Group'},{id:"B3",body:'Gu, T., Li, D., & Li, L. (2020). The Elderly’s demand for community-based care services and its determinants: A comparison of the elderly in the affordable housing community and commercial housing Community of China. Journal of Healthcare Engineering, 2020, 1840543. doi:10.1155/2020/1840543'},{id:"B4",body:'Santerre, R. E., & Neun, S. P. (2013). Health Economics: Theory, Insights, and Industry Studies: South-Western, Cengage Learning'},{id:"B5",body:'Wellay, T., Gebreslassie, M., Mesele, M., Gebretinsae, H., Ayele, B., Tewelde, A., & Zewedie, Y. (2018). Demand for health care service and associated factors among patients in the community of Tsegedie District, northern Ethiopia. BMC Health Services Research,18(1), 697. doi:10.1186/s12913-018-3490-2'},{id:"B6",body:'Wonderling, D. (2005). Introduction to Health Economics: McGraw-Hill Education'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Alireza Ghorbani",address:"ghorbania1474@yahoo.com",affiliation:'
Health Economics, Sabzevar University of Medical Sciences, Sabzevar, Iran
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1. Introduction
1.1 Mitochondria
Mitochondria are essential sub cellular mammalian organelles found in eukaryotes. It is surrounded by two lipid bilayers which is commonly associated with oxidative phosphorylation, a process that meets the majority of cellular energy demands. It is involved in many other cellular functions such as fatty acids oxidation, apoptosis, heme biosynthesis, metabolism of amino acids and lipids, and signal transduction [1]. They are central organelles controlling the life and death of the cell. Mitochondria contain their own DNA, which is maternally inherited. Mitochondrial density varies from one tissue to another [2]. Mitochondrial diseases are heterogeneous group of disorders, often characterized by morphological changes in the mitochondria, a defective respiratory chain and variable symptoms, ranging from severe metabolic disorders with onset in early infancy or childhood to late onset adult myopathies [3]. Mutations in mitochondrial DNA (mtDNA) are the most frequent cause of mitochondrial diseases in adults. However, the mtDNA encodes only a subset of proteins of the different complexes of the respiratory chain [4]. Nuclear genes encode all the other mitochondrial proteins and most of the mitochondrial disorders are caused by mutations in the nuclear genes [5].
Mitochondria are ~0.5 to ~3 μm long tubular organelles that undergo continuous remodeling of their network by fusion and fission events [6]. Mitochondria forms an extensive network preserved in many cells by an intricate balance between fission and fusion, mitochondrial biogenesis and mitophagy [7, 8]. Mitochondria was identified as the main source of cell energy, and indeed mitochondria is a major site of ATP and macromolecule development. Equivalent-reducing electrons are fuelled by the ETC to produce an electrochemical gradient required for both the production of ATP and the active transport of selective metabolites, such as pyruvate and ATP, through the IMM [9]. Mitochondria, however, plays a variety of roles beyond energy production, including generation of reactive oxygen species (ROS), redox molecules and metabolites, control of cell signaling and cell death, and biosynthetic metabolism.
While mitochondria is best known for harvesting and storage of energy released by oxidation of organic substrates under aerobic conditions by respiration, their many anabolic functions are often ignored [7]. Biosynthetic functions of mitochondria are essential for tumorigenesis and tumor progression [10]. Tumor cells easily survive under hypoxic conditions by recycling NADH to NAD+ through lactate dehydrogenase (LDH) and plasma membrane electron transport (PMET) to enable continued production of glycolytic ATP [11].
2. Mitochondrial genetics
The human mitochondrial genome consists of 16,569 pairs of nucleotides of double-stranded, closed-circular molecules. It was first sequenced in 1981 and updated in 1999 [12, 13]. mtDNA contains no introns and only encodes 13 polypeptides, 22 transfer RNAs (tRNAs), and the mitochondrial protein synthesis genes 12S and 16S rRNA [14]. The 13 polypeptides of the respiratory complexes (RC) encode subunits (7 of 45 for RC-I, 1 of 11 for RC-III, 3 of 13 for RC-IV, and 2 of 16 for RC-V). Along with the remaining 85% of the other RC subunits, the four subunits that make up RC-II are nuclear-encoded [14]. About 22,000 proteins are encoded by nuclear DNA, about 1,500 of which contribute to the mitochondrial proteome. These nuclear encoded proteins include TCA cycle enzymes, amino acids, nucleic acid and lipid biosynthesis, mtDNA and RNA polymerases, transcription factors, and ribosomal proteins, in addition to all DNA pathway repair components. In the cytoplasm, these proteins are expressed and folded through the TOM/TIM complex upon entry through the mitochondrial outer membrane. From there, they find the outer mitochondrial membrane (OMM), the IMM, the intermembrane space (IMS) or the mitochondrial matrix at their specific positions [15]. There is no structural association of mtDNA with histones, as is nuclear DNA. Rather, it is closely associated with a variety of proteins, about 100 nm in diameter, in discrete nucleoids.
Germline mutations resulting in reduced or lost expression of succinate dehydrogenase (SDH), fumarate hydratase (FH) and isocitrate dehydrogenase have been identified in inherited paragangliomas, gastrointestinal stromal tumors, pheochromocytomas, myomas, SDH, papillary renal cell cancer (FH) and gliomas [16]. mtDNA mutations have been involved in neuromuscular and neurodegenerative mitochondrial disease [17, 18, 19] and complex diseases such as diabetes [20], cardiovascular disease [21, 22], gastrointestinal disorders [23], skin disorders [24], aging [25, 26] and cancer. Different human populations have different human mtDNA haplotypes, each with a specific mtDNA polymorphism fingerprint, transmitted through the maternal germline. These haplotypes are associated with the geographic origin of the population. Some human haplotypes are at greater risk of developing a certain form of cancer or neurodegenerative disorder during their lifetime than others [27, 28, 29]. The 22 mitochondrial tRNA genes have more than 50 percent of the mtDNA mutations involved in carcinogenesis [29].
The single nucleotide polymorphism, 3243A > G, which alters leucine mt-tRNA and thus affects the translation of 13 respiratory subunits, leading to fewer mitochondrial subunits and impaired OXPHOS, is the most common mtDNA mutation [30, 31]. Individuals can develop maternally inherited diabetes and deafness with 10–30 percent defective copies of tRNALeu. Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) are likely to occur in people with 50–90% defective copies [20, 30, 31, 32, 33, 34, 35]. The mutation of tRNALeu results in variable types of mitochondrial RC deficiency in various patients. By far, complex I (RC-I) deficiency is the most common finding in MELAS, although some patients have combined RC-I, RC-III and RC-IV deficiencies [30, 36]. Other mutations in mt-tRNA that play a role in human disease include: tRNAlys, which is associated with myoclonal epilepsy, tRNASer with deafness, and tRNAIle with cardiomyopathy [21].
3. Drivers of mtDNA mutations
mtDNA mutations are caused by ROS-mediated oxidative damage [28, 37]. ROS generation in the respiratory chain is an inherent part of OXPHOS. ROS plays an important role in many signaling processes and their levels are regulated by the antioxidant enzyme systems in the mitochondrial matrix and the IMS. However, in situations where OXPHOS is compromised due to misshapen respiratory complexes resulting in increased leakage of electrons to oxygen, ROS levels can overwhelm the antioxidant protection system and damage to nearby mtDNA [38, 39]. DeBalsi and colleagues suggest that errors produced by mtDNA replication and repair machines may also cause mtDNA mutations [40].
Human cells contain 17 different human DNA polymerases, but in mtDNA replication and repair, only polymerase gamma (Pol-γ) functions. A catalytic subunit and an accessory subunit consist of a nuclear-encoded Pol-γ holo-enzyme [40]. Pol-γ replicates high fidelity mtDNA with one misinsertion in every 500,000 new base pairs due to nucleotide selectivity and proofreading capacity [41]. More than 300 Pol-γ mutations have been associated with human illness, some of which occur in adulthood and are associated with aging, including different types of progressive external ophthalmoplegia (PEO) and Parkinson’s disease (PD) [40]. The role of Pol-γ in restricting mtDNA mutations has been demonstrated by homozygous, but not heterozygous, mutator mice with re-reading-deficient Pol-g developing multiple age-related disorders and shortening their lifespan. As their antioxidant capacities were the same and the degree of oxidative damage was comparable to wild-type mice, they acquired mtDNA mutations that were not caused by oxidative damage.
Somatic point mutations, great deletions and several linear deleted mtDNA fragments were acquired by the mutator mice. The mtDNA-specific Twinkle helicase, which unwinds mtDNA for Pol-γ synthesis, is another n-mitoprotein involved in mtDNA replication [42]. Overexpression of Twinkle in transgenic mice resulted in increased copy number of mtDNA and OXPHOS and some twinkle mutations are associated with mitochondrial myopathy [40]. Oxidative damage and defective replication are both likely to add to the overall mutational load of the mtDNA cell, and the contribution of each mutational driver is likely to change over time. Inevitable respiratory electron leakage from complexes I and III results in the formation of superoxide, O2− that can react with lipids, proteins and DNA [43, 44, 45, 46]. Superoxide can be quickly converted to H2O2 either naturally or through a manganese superoxide dismutase (MnSOD) dysmutation reaction, a resident of the mitochondrial matrix. In the presence of redox active metal ions, H2O2 can generate a highly reactive hydroxyl radical through the Fenton reaction (OH-) [47]. Multiple mtDNA damage sites, including single and double-strand breaks, abasic sites and base changes, are responsible for the OH-radical. Another oxidative burden is caused by damage to mitochondrial protein centers caused by O2− to Fe-S and involves subunits of complexes I, II and III as well as aconitase [48, 49, 50]. A significant target for ROS is provided by Labile Fe-S enzymes such as mitochondrial aconitase.
Mitochondria located in cells exposed to visible light generate ROS through interactions with mitochondrial photosensitizers, such as cytochrome c oxidase, of particular relevance to the eye, to produce ROS and mtDNA damage [50, 51]. Transferring energy from photoactivated chromophores to oxygen contributes to the formation of singlet oxygen, 1O2, which occurs in an excited state. 1O2 can produce ROS, such as O2− by interacting with diatomic oxygen and directly reacting with dual-bond electrons without the formation of free radical intermediates [52]. It is also important to remember that, from non-mitochondrial sources, various tissues within the eye may also produce substantial amounts of ROS. For instance, lipofuscin (an age-related pigment that accumulates with age in RPE cells) is a potent photoinducible ROS generator, and NADPH oxidase is considered to be a major source of superoxide in microvascular endothelial cells. Studies indicate that ROS may also contribute to exogenous mitochondrial oxidative damage, exacerbating mitochondrial dysfunction [51, 53, 54].
4. Ophthalmologic mitochondrial dysfunction
Mitochondrial disease can manifest in any organ at any age. In general terms, tissues and organs (retina, optic nerve, brain, heart, testis, muscle, etc.) that are heavily dependent upon oxidative phosphorylation bear the brunt of the pathology. It is also puzzling that many mitochondrial disorders affect multiple organ systems, whereas others have a highly stereotyped and organ specific phenotype. These subtle interactions between nuclear and mitochondrial genes in health and disease will have broader relevance for our understanding of many inherited and sporadic disorders.
Mitochondrial disorder can be categorized according to several different criteria in the manifestations of ophthalmology diseases. They may be defined as isolated or nonisolated, occurring in combination with other manifestations of the organ. The dominant trait of the phenotype or a nondominant attribute can be ophthalmologic manifestations. Mitochondrial disorders with ophthalmic manifestations may be caused either by mutations in mtDNA or nuclear DNA. Ophthalmologic symptoms may be unique to syndromic mitochondrial disorder (e.g. Leber hereditary optic neuropathy) or nonspecific to syndromic mitochondrial disorder (eg, cataract). The cornea, iris, lens, ciliary body, retina, choroid, uvea, or optic nerve may be the primary manifestations of ophthalmologic mitochondrial disorder. There is growing evidence supporting an association between mitochondrial dysfunction and a number of ophthalmic diseases causing defects in OXPHOS and increased production of ROS triggering the activation of cell death pathway.
5. Corneal dystrophy
Some evidence has been given in recent years that the cornea may be involved in mitochondrial disorders. However, systematic studies have not been performed on this matter. Astigmatism, corneal dystrophy, corneal clouding, or corneal endothelial dysfunction are corneal disorders associated with mitochondrial dysfunction [55, 56]. Loss of SLC4A11 gene activity which is localized to the inner mitochondrial membrane of corneal endothelium, induces oxidative stress and cell death, resulting in Congenital Hereditary Endothelial Dystrophy (CHED) with corneal edema and vision loss [57]. Fuchs endothelial corneal dystrophy (FECD) is characterized by progressive and non-regenerative corneal endothelial loss. Variations in mtDNA affect the susceptibility of FECD. Mitochondrial variant A10398G and Haplogroup I were significantly associated with FECD [58]. There are few studies showing the role of mtDNA in the pathogenesis of FECD. Mitophagy activation leads to decrease in Mfn2 gene level and loss of mitochondrial mass in FECD [59]. In a study of 20 patients, keratoconus was related to increased oxidative stress due to mitochondrial respiratory chain complex-I sequence variation [60]. Progressive external ophthalmoplegia secondarily led to persistent conjunctivitis and keratitis in a patient with Kearns-Sayre Syndrome [61]. Corneal clouding has been documented occasionally in Kearns-Sayre syndrome due to structural changes in the endothelium or Descemet membrane [62]. Numerous distended mitochondria were present in the corneal epithelium in a child with Leigh syndrome due to the m.8993 T > G mutation [63]. There are also non-specific corneal alterations in a patient with Neurogastrointestinal mitochondrial encephalomyopathy [64]. Pathogenesis of type 2 granular corneal dystrophy (GCD2) is associated with alteration of mitochondrial features and functions that causes mutated GCD2 keratocytes, particularly in older cells [65].
6. Mitochondrial encephalomyopathy, lactic acidosis, and episodic stroke-like syndrome (MELAS)
Early onset of the disease and higher level of mtDNA heteroplasmy are associated with a worse prognosis in mitochondrial encephalomyopathy, lactic acidosis, and episodic stroke-like syndrome (MELAS). Iris involvement in mitochondrial disorders has been rarely mentioned in MELAS [66]. The m.3243A > G variant is the most common heteroplasmic mtDNA mutation in MELAS and underlies a spectrum of diseases. Patchy iris stroma atrophy has been identified in a patient carrying the m.3243A > G mutation in the tRNA (Lys) gene [66]. MNRR1 (CHCHD2) is a bi-organellar regulator of mitochondrial function, found to be depleted in MELAS and significantly associated with m.3243A > G mutation (heteroplasmic) in the mtDNA at a level of ∼50 to 90% [67]. Ability of the peroxisome proliferator-activated receptor γ (PPARγ) activator pioglitazone (PioG), in combination with deoxyribonucleosides (dNs), improves the mitochondrial biogenesis/respiratory functions in MELAS cybrid cells containing >90% of the m.3243A > G mutation that found to be novel therapies to treat this disease [68]. Induced pluripotent stem cells (iPSCs) are appropriate for studying mitochondrial diseases caused by mtDNA mutations in MELAS. Increase of autophagy inpatient-specific iPSCs generated from fibroblasts are associated with mtDNA mutations and OXPHOS defects in patients with MELAS [69]. Studies demonstrated that defective MRM2 gene causes a MELAS-like phenotype which suggests the genetic screening of the MRM2 gene in patients with a m.3243 A > G negative MELAS-like presentation [70]. Mutations caused by mitochondrial complex I deficiencies by alleviating ketone bodies are also associated with MELAS that leads to recurrent cerebral insults resembling strokes [71].
7. Cataract
Cataracts are the most common lenticular defects of mitochondrial disorders. In mitochondrial disorders, cataract is typically of the posterior subcapsular type [66]. Autophagic dysfunction and abnormal oxidative stress are associated with cataract. Cataract may be a phenotypic characteristic of MELAS syndrome, but a patient with nonsyndromic mitochondrial disorder due to mtDNA deletion has also been documented as an initial manifestation [66, 72, 73]. Oxidative stress plays an important role in cataractogenesis [74, 75]. Mitochondria are found in the epithelium and superficial fiber cells of the lens and it is extremely sensitive to ROS. Interestingly, mitochondria have been confirmed as the main source of ROS generation in these cell types [76]. A number of in vitro studies have shown that human lens cells are particularly sensitive to oxidative insults, where antioxidant activity was inversely proportional to the severity of cataracts [77]. Proteins, lipids and DNA oxidation have been found in cataract lenses [78, 79, 80]. Under high glucose conditions, fluctuations in autophagy and oxidative stress are found in mouse lens epithelial cells (LECs) that might attenuate high glucose-induced oxidative injury to LECs [81]. Cataract proteins lose sulfhydryl groups, contain oxidized residues, produce aggregates of high molecular weight and become insoluble [75]. In addition, cataract has been shown to be a symptom of a newly identified mitochondrial disorder called autosomal recessive myopathy, caused by growth factor mutations, increased liver regeneration gene, which affects protein levels of mitochondrial intermembrane space region [82].
8. Leigh syndrome
In mitochondrial disorders, involvement of ciliary body has rarely been reported. Leigh’s syndrome is the most common pediatric syndrome, characterized by symmetrical brain lesions, hypotonia, motor and respiratory deficits, and premature death are associated with pathways involved in mitochondrial diseases [83]. A case report showed ocular histopathological finding such as thinning of nerve fibers and ganglion cell layers in the nasal aspect of the macula, mild atrophy of the temporal aspect of the optic nerve head, and numerous distended mitochondria, non-pigmented cilla are associated with the m.8993 T > G mutation in the ATPase6 gene of mtDNA in patient with Leigh’s syndrome [63]. In addition, ciliary epithelium was also found to be impaired by a long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency [84]. Dysfunction of mitochondrial complex I are also associated with many brain pathologies including Leigh’s syndrome. Mitochondrial complex I activity facilitates organismal survival by its regeneration potential of NAD+, while optimal motor regulation involves mitochondrial complex I bioenergetic function in Leigh’s syndrome [85].
9. Retinitis pigmentosa
Retinitis pigmentosa is a central characteristic of Kearns-Sayre syndrome and neuropathic ataxia retinitis pigmentosa syndrome [72]. Typical for Kearns-Sayre syndrome is ‘salt and pepper’ retinitis, with areas of increased and decreased pigmentation, especially in the equatorial fundus [62]. Pigment retinopathy is only an uncommon characteristic of progressive external ophtalmoplegia and can be milder than in Kearns-Sayre syndrome [72, 86]. Only certain patients with MELAS or MERRF syndrome have mild posterior pole pigment retinopathy [72]. Mild pigmentary defects were also observed in 2 of 20 patients with Leber hereditary optic neuropathy due to mutation m.11778G > A [72]. Small pigment retinal defects have been identified in a 4-year-old female with a COX deficiency [87]. In addition, because of the mutation m.8993 T > GG retinitis pigmentosa has been identified in patients with Leigh syndrome [88].
In a sample of 44 Korean Leigh syndrome patients, pigmentary retinopathy was also observed in 22% of Korean patients [89]. In a study of 14 patients with pontocerebellar hypoplasia, 4 patients presented with retinopathy without disclosing information [90]. Occasionally, retinal dystrophy can manifest with photophobia. In a report of 46 mitochondrial disease patients, 4 had photophobia. Two patients had Leigh syndrome, 1 of which had rod-cone dystrophy on electroretinography, 1 had Kearns-Sayre syndrome with regular electroretinography, and 1 had MERRF syndrome with isoelectric electroretinography [91].
10. Diabetic retinopathy
It has been shown that mitochondrial dysfunction plays a significant role in diabetic retinopathy [92, 93]. Hyperglycemia causes retinal mitochondrial damages that plays a central role in the development of diabetic retinopathy. Retinal mitochondria undergo elevated oxidative stress in diabetes, and complex III is one of the key causes of increased O2− [94]. Superoxide levels are elevated in in the retina of diabetic rats and in retinal vascular endothelial cells incubated in high-glucose media [95] and the content of hydrogen peroxide is also increased in the retina of diabetic rats [96]. In diabetes, membrane lipid peroxidation and oxidative DNA damage, the effects of ROS-induced injury, are elevated in the retina [97]. Chronic overproduction of ROS in the retina results in aberrant mitochondrial functions in diabetes [92]. Overproduction of superoxide by the mitochondrial electron transport chain caused by hyperglycemia is considered to cause major hyperglycemic damage pathways by inhibiting the action of GAPDH. However, it is not yet fully understood the mechanism by which hyperglycemia induces an increase in mitochondrial ROS, with some suggesting a direct effect and others an indirect function via high-glucose-induced cytokines [98, 99, 100, 101].
Elevated levels of O2− activate caspase 3 in retinal capillaries contributes to cell death [92]. Upregulation of superoxide dismutase (SOD2) inhibited increased mitochondrial O2-induced diabetes, restored mitochondrial function, and prevented both in vitro and in vivo vascular pathology [94, 102, 103, 104]. However, the timing of such therapies is important because animal studies have shown that oxidative stress not only leads to the development of diabetic retinopathy, but also to the resistance of retinopathy to reversal [105]. The resistance to reversal of diabetic retinopathy may be due to the accumulation of weakened mitochondrial molecules and ROS-induced damage that is not readily removed even after the restoration of high glycemic control. However, the accumulation of advanced glycation end products is also involved in metabolic memory [106]. The mtDNA variation has also been associated with resistance to type 1 diabetes. A single nucleotide modification (C5173A) is associated with resistance to type 1 diabetes in the Japanese population, resulting in a leucine-to-methionine amino acid substitution in the mitochondrially encoded NADH dehydrogenase subunit 2 gene [107]. Similarly, in comparison with the diabetes-prone nonobese diabetic mouse strain, orthologous polymorphism (C4738A), resulting in L-to-M substitution, offers resistance against the development of spontaneous diabetes [108]. Gusdon et al., have shown that the replacement of methionine results in a lower level of development of ROS from complex III [109].
The product of mtDNA mutations is also known to result in many syndromic central nervous system diseases. The most common retinal pathology is pigmentary retinopathy, while optic neuropathy is an uncommon finding in these disorders. Neurogenic atrophy and retinitis pigmentosa syndrome results from point mutations in the mtDNA ATPase-6 gene, usually T8993G variation. Patients usually present with retinitis pigmentosa with or without optic neuropathy and may develop dystonia [110]. Several mtDNA point mutations may result from MELAS, although the A3243G mutation in the tRNALeu gene is the most common. Patients with MELAS undergo stroke-like episodes leading to recurrent retrochiasmal vision loss, but sometimes even to pigmentary retinopathy without optic atrophy [111]. Its contribution to the pathogenesis of maternally inherited diabetes and deafness is also evidenced by the spectrum of disease resulting from the A3243G point mutation [112, 113, 114]. This is a multisystemic disease characterized by sensorineural deafness, retinal defects and diabetes, generally occurring in the third to fourth decades of life [115]. The second phenotype is a pattern dystrophy, with diffuse granularity and pigment clumping, marked by relative sparing of the fovea, and retinal pigment epithelium within the vascular retinal arcades. However, with a strong prognosis, visual acuity is retained, despite the degree of atrophy [116, 117].
11. Macular degeneration
Age-related macular degeneration is a neurodegenerative late-onset disorder that shares certain characteristics of Alzheimer’s disease. In most cases, the build-up of protein plaques, known as drusen, in the central macular area of the retina involves age-related macular degeneration. Both age-related macular degeneration and Alzheimer’s disease pathogenesis can be driven by stress stimuli, including oxidative stress, aging, genetic factors and inflammation, including the deposition of protein plaques in the retina or brain [98]. Similarities in these two disorders are also found in the risk factor gene polymorphisms, APOE, associated with age-related macular degeneration [99, 100] and Alzheimer’s disease [101, 102]. The APOE gene controls the homeostasis of triglycerides and cholesterol [103], and the loss of function of APOE has been correlated with the deposit of senile plaques, consisting mainly of amyloid beta peptide [104], which is produced in drusen [105, 106] and is also associated with an additional risk factor for age-related macular degeneration, i.e. complement protein [107, 108]. Evidence shows that the APOE genotype can dictate the risk of stress stimuli, including oxidative stress, aging, genetic factors and inflammation, including the deposition of protein plaques in the retina or brain, can drive both age-related macular degeneration and Alzheimer’s disease pathogenesis. Alzheimer’s disease and other chronic disorders, primarily because of its effect on regulation of oxidative stress [109]. Age-related macular degeneration is split into two main forms, i.e. the “wet” form induced by leakage into the subretinal space from choroidal neovascularization and the more common “dry” form associated with the accumulation of drusen in the macula [75]. In patients with age-related macular degeneration, there is an increased incidence of large-scale mtDNA rearrangements and deletions in blood [76] and retinas [77, 78]. In the non-coding mtDNA control area (d-loop) in retinas with age-related macular degeneration, which has been found in Alzheimer’s disease and other conditions of oxidative stress, there are also increased rates of single nucleotide polymorphisms [79]. An increased rate of mtDNA deletions and single nucleotide polymorphisms are likely to decrease the amount and density of mitochondria [80].
Other than pigmentary retinopathy or macular degeneration, retinal anomalies include retinal dystrophy, retinal hypertrophy, and pigmentary maculopathy. Patients with Kearns-Sayre syndrome, Leigh syndrome, MELAS syndrome, MERRF syndrome, and Leber hereditary optic neuropathy will find retinal dystrophies that are most easily measured by electroretinography [91]. Retinal hypertrophy has been identified in patients with autosomal recessive spastic ataxia with leukoencephalopathy and autosomal recessive spastic ataxia with Charlevoix-Saguenay (ARSAL/ARSACS) [118]. Six affected males in a family with Mohr-Tranebjaerg syndrome had blindness resulting from unexplained retinal degeneration [119]. Treatment options for retinopathy are usually limited.
12. Choroidal dystrophy
Choroid and uvea are occasionally affected by mitochondrial disorders. Choroid atrophy is the most common manifestation of mitochondrial disorders [66]. Choroidal atrophy was especially identified in the sense of MELAS syndrome [66]. Choroid pigment epithelium atrophy also occurs in maternally inherited deafness and diabetes [120]. Central choroidal dystrophy was identified in 1 patient with Mohr-Tranebjaerg syndrome as confirmed by electroretinography [119]. In addition, chorioretinal dystrophy was reported in a single patient with a significant deletion of mtDNA [121].
13. Uveitis
A significant causative factor causing blindness from retinal photoreceptor degeneration is intraocular inflammation, also referred to as uveitis. Activated macrophages, which generate various cytotoxic agents, including inducible nitric oxide generated by inducible nitric oxide synthase, O2− and other ROS, are responsible for oxidative retinal damage in uveitis [122]. Oxidative stress plays an important role in the early stages of experimental autoimmune uveitis (EAU) in the photoreceptor mitochondria. mtDNA damage has been shown to occur early in the EAU; interestingly, nDNA damage occurred later in the EAU [123]. In addition, peroxynitrite-mediated nitration modifies mitochondrial proteins in the inner segments of the photoreceptor, which, in turn, contributes to increased mitochondrial ROS generation [124]. MnSOD has been shown to be upregulated during EAU to promote an increased state of mitochondrial oxidative stress, possibly to combat ROS [125]. In the early phase of the EAU, before leukocyte infiltration, recent data seem to indicate a causative function of oxidative mtDNA harm. Such mitochondrial oxidative damage can be the initial event that contributes to retinal degeneration in uveitis [123].
14. Optic atrophy
Optic atrophy is the principal mitochondrial dysfunction manifestation of the optic nerve. Optic atrophy is a prevalent manifestation of mitochondrial disorder but is often overlooked or misinterpreted. This is due to the difficulties of optic atrophy diagnosis. Funduscopy can more reliably determine optic atrophy if the distal portion of the optic nerve is impaired, or if the more proximal portions of the nerve are affected by orbital magnetic resonance imaging (MRI). A decreased amplitude of visually evoked potential is a sign of optic nerve atrophy [126]. Optic atrophy has been specifically identified in Leber hereditary optic neuropathy and autosomal dominant optic atrophy among syndromic mitochondrial disorders, conditions in which optic atrophy is the dominant phenotypic function [127]. MELAS syndrome, Kearns-Sayre syndrome, Pearson syndrome, pontocerebellar hypoplasia, Mohr-Tranebjaerg syndrome, Alpers-Huttenlocher disease or Wolfram syndrome have been documented more rarely, with optic atrophy [62, 90, 91, 127]. In patients with MERRF syndrome, partial or complete optic atrophy has also been identified [72, 91, 128]. Optical atrophy is a common phenotypic characteristic of inherited motor and sensory neuropathy type VI (HMSN-IV) due to MFN1 mutations [127]. In addition, C12orf65 (COXPD7) mutations manifest phenotypicly with optical atrophy and Leigh-like phenotype [129]. Optical atrophy associated with neuropathy ataxia retinitis pigmentosa syndrome due to m.8993 T > G mutation in the ATPase6 gene was only seen in a single family [110]. In a study of 44 Korean patients with Leigh Syndrome, 22.5 per cent of optical atrophy was identified [89]. Optical disk alterations have been observed only in a single patient with mitochondrial neurogastrointestinal encephalomyopathy [64]. Optical atrophy can also be a characteristic of childhood-onset spinocerebellar ataxia [130] or mitochondrial depletion syndrome. 39 Non-syndromic mitochondrial optic atrophy disorders is attributed to ACI1 mutation [131], due to ND5 mutation with cataract and retinopathy [132].
15. Glaucoma
Increased intraocular pressure (Glaucoma) is an unusual phenotypic characteristic of mitochondrial disorders. There are two primary types of glaucoma that can be distinguished, open-angle glaucoma and closed-angle glaucoma. In addition, normotensive and hypertensive glaucoma are distinguished. Open-angle glaucoma is seldom observed in patients with Leber inherited optic neuropathy or autosomal dominant optic atrophy. Funduscopic findings can indicate a mixture of abnormalities common for glaucoma retinopathy and an inherited Leber optic neuropathy fundus [133]. In a single patient with mitochondrial neurogastrointestinal encephalomyopathy, glaucomatous changes in the optic disc were observed by visual field assessment and optical coherence tomography [64]. In a study of 14 patients with pontocerebellar hypoplasia, one presented with glaucoma [90]. Normal pressure glaucoma is associated with polymorphism in the OPA1 gene [134].
Glaucoma has also been identified in a family with Wolfram Syndrome. There are signs that ND5 mutations are associated with the development of open-angle glaucoma. Glaucoma in mitochondrial disorders may be eligible for treatment with drugs or surgery [135, 136]. There is evidence in glaucoma that mitochondrial dysfunction can reduce the bioenergetic status of retinal ganglion cells, leading to increased susceptibility to oxidative stress and apoptotic cell death [93, 137]. Light exposure may also be an oxidative risk factor, reducing mitochondrial function and increasing the development of ROS in ganglion cells [138]. A defective mitochondria has been highly implicated in neuronal apoptosis in the experimental models of glaucoma [139, 140]. The mtDNA abnormalities further support the importance of mitochondrial dysfunction-associated stress as a risk factor for glaucoma patients [141].
16. Nystagmus
The central nervous system or vestibular involvement in mitochondrial disorders may cause nystagmus or roving eye movements and are the most common ophthalmological manifestations as a symptom in patients with pediatric mitochondrial disorder [142]. A Gaze-evoked nystagmus identified in a single patient with “Leber hereditary optic neuropathy plus” who not only possessed the “m.11778G > A” mutation in the hereditary Leber hereditary optic neuropathy gene but also the “m.3394 T > C” mutation [143]. Since patients with MELAS may display irregular eye movements on an eye movement cueing task, ultrasound records of eye movement may show abnormally slow saccadic reactions, prolonged saccades, impaired suppression of reflex eye movements, prolonged reaction during antisaccades, square-wave jerks, or impaired chase [144]. Patients have epilepsy due to MELAS may have epileptic nystagmus, disrupted smooth pursuit, or transient eye divergence, none of which are outward signs [145]. In addition, nystagmus was documented in a patient carrying a point mutation in the DGUOK gene who also had retinal blindness. Nystagmus, which is a common symptom of the disease along with retinitis pigmentosa, was also reported in a patient with nonsyndromic mitochondrial disorder due to the m.15995G > A mutation in the tRNA (Pro) gene manifesting as ataxia, deafness, and leukoencephalopathy [146]. Nystagmus was part of the phenotype in a study of 7 Czech patients with autosomal dominant optic atrophy [147]. Nystagmus is also a common characteristic of ARSAL/ARSACS [148]. Nystagmus was observed in 14 percent in a study of 44 Korean patients with Leigh syndrome [88].
17. Strabismus
Strabismus was the most common ophthalmologic abnormality in a study of 44 Korean patients with Leigh syndrome and was present in 41% of patients [89]. Of the strabismus patients, 13 had exotropia and 5 had esotropia [89]. In some patients with X-linked sideroblast anemia with ataxia, strabismus has also been identified [149]. In 25 percent of juvenile mitochondrial disorders, divergent strabismus has been identified as the presenting manifestation [150]. In a study of 14 patients with pontocerebellar hypoplasia, of whom 13 had a CASK mutation, 2 had strabismus. 9 Strabismus was also identified without knowing the underlying mutation in other patients with pontocerebellar hypoplasia [151, 152]. The initial presentation at birth was cataract and strabismus in a child with a significant mtDNA deletion. Later on, he experienced Leigh-like pathologies and episodes of stroke [153]. In certain instances, surgery can have a beneficial effect on strabism.
18. Progressive external ophthalmoplegia
In mitochondrial disorders, affectation of the extraocular muscles results in progressive external ophthalmoplegia. The recurrent ophthalmologic manifestation of mitochondrial disorders is progressive external ophthalmoplegia. It may be complete, resulting in, or partial, walled-in bulbs. Both directions of bulb movements or only some of them can be affected. One eye or both eyes can be affected by it. Single or multiple mtDNA deletions are most often associated with progressive external ophthalmoplegia. Progressive external ophthalmoplegia, Kearns-Sayre syndrome or Pearson syndrome can cause single mtDNA deletions [154]. Multiple deletions of mtDNA may be due to mutations in nuclear genes such as PEO1, POLG1, SLC25A4, RRM2B, POLG2, or OPA1, along with progressive external ophthalmoplegia [154]. In addition, progressive external ophthalmoplegia, especially in the transfer of RNA (eg, tRNA(Lys)) genes, may be due to mtDNA point mutations [154]. Transfer RNA mutations with progressive external ophthalmoplegia are mostly sporadically similar to mtDNA deletions and can only be observed in muscle deletions [155]. The sole manifestation of the m.3243A > G mutation, which often manifests as MELAS syndrome, may be progressive external ophthalmoplegia [156]. In a patient with mitochondrial neurogastrointestinal encephalomyopathy, progressive external ophthalmoplegia was a phenotypic feature [64], Wolfram syndrome [157], Leigh syndrome, autosomal dominant optic atrophy, and mitochondrial recessive ataxia syndrome. In MERRF syndrome, progressive external ophthalmoplegia has also been described [158].
Infantile-onset spinocerebellar ataxia is a Finnish disorder, with some of the 24 cases identified to date developing ophthalmoplegia [130]. Ophthalmoparesis is a hallmark of sensory ataxic neuropathy with ophthalmoparesis syndrome and dysarthria [159]. Sensory ataxic neuropathy with dysarthria and ophthalmoparesis is due to mutations in either the POLG1 or PEO1 gene resulting in multiple mtDNA deletions [159]. Furthermore, ophthalmoparesis can be observed in patients with mitochondrial depletion syndrome [160] or nonsyndromal mitochondrial disorders [161]. In patients with Leber inherited optic neuropathy and progressive external ophthalmoplegia, ultrastructural variations in muscle biopsy from the extraocular muscles clearly differ [162].
19. Eyelid
Ptosis is one of the most common forms of mitochondrial dysfunction. It can occur unilaterally at onset, but during the course of the disease, it usually becomes bilateral. Ptosis can be the sole manifestation, particularly at the onset of the disease, of a mitochondrial disorder or associated with other manifestations. Particularly at the onset of the disease, ptosis can show dynamic alterations, leading to misinterpretation as myasthenia gravis [163]. Ptosis may be discrete, especially at initiation, so that it is missed on clinical review. Progressive external ophthalmoplegia or other ocular symptoms of mitochondrial disease can be associated with ptosis. Ptosis of syndromic as well as nonsyndromic mitochondrial disorders may be a phenotypic manifestation. In particular, ptosis was identified in progressive external ophthalmoplegia, MELAS, MERRF, Kearns-Sayre syndrome, sensory ataxic neuropathy with dysarthria and ophthalmoparesis [164], Pearson syndrome, mitochondrial neurogastrointestinal encephalomyopathy, and autosomal dominant optic atrophy, among the syndromic mitochondrial disorders [91]. Ptosis was present in 16 percent in a group of 44 Korean patients with Leigh syndrome [89]. Ptosis was also present in isolated cases of maternally inherited deafness and diabetes [156], mitochondrial neurogastrointestinal encephalomyopathy [64], or mitochondrial depletion syndrome [160]. Poor lid closure was found in a Persian Jew with mitochondrial myopathy, lactic acidosis, and sideroblastic anemia due to a PUS1 mutation [165].
20. Leber hereditary optic neuropathy
Leber hereditary optic neuropathy is a maternally inherited blindness condition caused by gene mutations encoding the respiratory-chain complex I subunits. Nearly 90 percent of all cases of Leber inherited optic neuropathy contain mutations in 3 genes [128]. The m.3460A > G mutation in the ND1 gene, the m.11778G > A mutation in the ND4 gene and the m.14484 T > C mutation in the ND6 gene are the 3 most common Leber hereditary optic neuropathy mutations (primary Leber hereditary optic neuropathy mutations) [128]. Leber inherited optic neuropathy is clinically characterized as bilateral, painless, subacute vision impairment that occurs during young adult life [134].
Compared with women, Leber hereditary optic neuropathy is 4 to 5 times more common in males. Individuals affected are usually completely asymptomatic until they experience visual blurring in 1 eye affecting the central visual field [134]. On average, 2 to 3 months later, similar signs develop in the other eye. In most cases, visual acuity is greatly diminished or even worse when counting fingers, and visual field examination reveals an expanded central or ceco-central thick scotoma [134]. After the acute process, the optical disks become atrophic. Funduscopic findings characteristic of Leber inherited optic neuropathy include microangiopathy, hyperemic disks, retinal telangiectasis (ectatic capillaries), peripapillary microangiopathy, and tortuosity of vessels (twisted vessels). (twisted vessels). The orbital MRI can display atrophy of the nerve with a compensated widening of the space below the optic sheath. Mutations in mitochondrial ND3, ND4, or ND6 genes can cause hereditary Leber optic neuropathy with dystonia [166].
21. Autosomal dominant optic atrophy
Autosomal dominant optic atrophy is a blindness condition which does not display a gender disparity, unlike Leber inherited optic neuropathy [127]. It is caused by mutations in the nuclearly encoded OPA1 gene [127]. Autosomal dominant optic atrophy can also be due to OPA3 mutations that are associated with cataract [167]. Progressive, painless, bilateral symmetrical vision loss clinically characterizes autosomal dominant optic atrophy [154]. Central, ceco-central, or para-central scotomas, consistent with early involvement of the papillo-macular bundle, are the most common visual field anomalies in autosomal dominant optic atrophy [154]. OPA1 mutations can manifest not only with optic atrophy in some families, but also with progressive external ophthalmoplegia, ptosis, and hypoacusis [168]. Since glaucoma neuropathy, autosomal dominant optic atrophy, and Leber hereditary optic neuropathy often have similar changes in the topographic optic disc, they cannot be discriminated against alone by disc evaluation [169]. There is currently no appropriate treatment available.
22. Retinoblastoma
Retinoblastoma (Rb) is the most common intraocular cancer in children that arise from retinal precursor cells. Electron microscopy revealed numerous morphological and pathological changes in mitochondria of retinoblastoma patients. Cristolysis and degenerated mitochondria were the most frequently observed features in Rb [170]. A study suggested that T16519C, C16223T, A263G and A73G mtDNA D-Loop mutations plays a significant role in the etiology of retinoblastoma. This was the first study to examine the mtDNA D-loop mutation in retinoblastoma and its correlation with various parameters and patient outcome [171]. Their findings imply a strong inhibition of mitochondrial oxidative phosphorylation complexes in these patients. Loss of mitochondrial complex I was found in majority of the cases whereas expression of mitochondrial complex III, IV and V were found in more than 50% of the cases. Expression of mitochondrial complex I was associated with good prognosis and better overall survival [172]. Another consequence of alteration in OXPHOS complexes is an increased production of reactive oxygen species (ROS). NADPH oxidases (NOX4) are a major intracellular source of ROS and it was found to be overexpressed in retinoblastoma [173]. Increased expression of ROS and decreased expression of OXPHOS complexes modulates the apoptotic pathway involved in mitochondria by altering BCl-2 family proteins. Singh et al. showed a differential expression of apoptotic regulatory proteins (Bax, BCl-2, PUMA and p53) where they found increased expression of BCl-2 and PUMA along with loss of Bax and p53, which might contribute to carcinogenesis in Rb [174].
23. Conclusion
Researchers found that these findings are important because they indicate that mtDNA damage can be caused by both spontaneous ROS and by inherited mtDNA mutations. Continued study in this clinically important area would certainly provide a better understanding of how deficiencies/mutations of the mitochondrial genome contribute to the pathogenesis of ocular diseases. The biggest problems with the future of mitochondria are the advancement of therapeutic strategies to target mitochondria and modify its DNA using nucleotide precursors to retain mitochondrial integrity. These therapeutic strategies can potentially be used to block or slow down the effects of mitochondrial disease in future.
Department of Dermatology, University of Wisconsin, USA
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The company was founded in Vienna in 2004 by Alex Lazinica and Vedran Kordic, two PhD students researching robotics. While completing our PhDs, we found it difficult to access the research we needed. So, we decided to create a new Open Access publisher. A better one, where researchers like us could find the information they needed easily. The result is IntechOpen, an Open Access publisher that puts the academic needs of the researchers before the business interests of publishers.
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We started by publishing journals and books from the fields of science we were most familiar with - AI, robotics, manufacturing and operations research. Through our growing network of institutions and authors, we soon expanded into related fields like environmental engineering, nanotechnology, computer science, renewable energy and electrical engineering, Today, we are the world’s largest Open Access publisher of scientific research, with over 4,200 books and 54,000 scientific works including peer-reviewed content from more than 116,000 scientists spanning 161 countries. Our authors range from globally-renowned Nobel Prize winners to up-and-coming researchers at the cutting edge of scientific discovery.
\\n\\n
In the same year that IntechOpen was founded, we launched what was at the time the first ever Open Access, peer-reviewed journal in its field: the International Journal of Advanced Robotic Systems (IJARS).
\\n\\n
The IntechOpen timeline
\\n\\n
2004
\\n\\n
\\n\\t
Intech Open is founded in Vienna, Austria, by Alex Lazinica and Vedran Kordic, two PhD students, and their first Open Access journals and books are published.
\\n\\t
Alex and Vedran launch the first Open Access, peer-reviewed robotics journal and IntechOpen’s flagship publication, the International Journal of Advanced Robotic Systems (IJARS).
\\n
\\n\\n
2005
\\n\\n
\\n\\t
IntechOpen publishes its first Open Access book: Cutting Edge Robotics.
\\n
\\n\\n
2006
\\n\\n
\\n\\t
IntechOpen publishes a special issue of IJARS, featuring contributions from NASA scientists regarding the Mars Exploration Rover missions.
\\n
\\n\\n
2008
\\n\\n
\\n\\t
Downloads milestone: 200,000 downloads reached
\\n
\\n\\n
2009
\\n\\n
\\n\\t
Publishing milestone: the first 100 Open Access STM books are published
\\n
\\n\\n
2010
\\n\\n
\\n\\t
Downloads milestone: one million downloads reached
\\n\\t
IntechOpen expands its book publishing into a new field: medicine.
\\n
\\n\\n
2011
\\n\\n
\\n\\t
Publishing milestone: More than five million downloads reached
\\n\\t
IntechOpen publishes 1996 Nobel Prize in Chemistry winner Harold W. Kroto’s “Strategies to Successfully Cross-Link Carbon Nanotubes”. Find it here.
\\n\\t
IntechOpen and TBI collaborate on a project to explore the changing needs of researchers and the evolving ways that they discover, publish and exchange information. The result is the survey “Author Attitudes Towards Open Access Publishing: A Market Research Program”.
\\n\\t
IntechOpen hosts SHOW - Share Open Access Worldwide; a series of lectures, debates, round-tables and events to bring people together in discussion of open source principles, intellectual property, content licensing innovations, remixed and shared culture and free knowledge.
\\n
\\n\\n
2012
\\n\\n
\\n\\t
Publishing milestone: 10 million downloads reached
\\n\\t
IntechOpen holds Interact2012, a free series of workshops held by figureheads of the scientific community including Professor Hiroshi Ishiguro, director of the Intelligent Robotics Laboratory, who took the audience through some of the most impressive human-robot interactions observed in his lab.
\\n
\\n\\n
2013
\\n\\n
\\n\\t
IntechOpen joins the Committee on Publication Ethics (COPE) as part of a commitment to guaranteeing the highest standards of publishing.
\\n
\\n\\n
2014
\\n\\n
\\n\\t
IntechOpen turns 10, with more than 30 million downloads to date.
\\n\\t
IntechOpen appoints its first Regional Representatives - members of the team situated around the world dedicated to increasing the visibility of our authors’ published work within their local scientific communities.
\\n
\\n\\n
2015
\\n\\n
\\n\\t
Downloads milestone: More than 70 million downloads reached, more than doubling since the previous year.
\\n\\t
Publishing milestone: IntechOpen publishes its 2,500th book and 40,000th Open Access chapter, reaching 20,000 citations in Thomson Reuters ISI Web of Science.
\\n\\t
40 IntechOpen authors are included in the top one per cent of the world’s most-cited researchers.
\\n\\t
Thomson Reuters’ ISI Web of Science Book Citation Index begins indexing IntechOpen’s books in its database.
\\n
\\n\\n
2016
\\n\\n
\\n\\t
IntechOpen is identified as a world leader in Simba Information’s Open Access Book Publishing 2016-2020 report and forecast. IntechOpen came in as the world’s largest Open Access book publisher by title count.
\\n
\\n\\n
2017
\\n\\n
\\n\\t
Downloads milestone: IntechOpen reaches more than 100 million downloads
\\n\\t
Publishing milestone: IntechOpen publishes its 3,000th Open Access book, making it the largest Open Access book collection in the world
We started by publishing journals and books from the fields of science we were most familiar with - AI, robotics, manufacturing and operations research. Through our growing network of institutions and authors, we soon expanded into related fields like environmental engineering, nanotechnology, computer science, renewable energy and electrical engineering, Today, we are the world’s largest Open Access publisher of scientific research, with over 4,200 books and 54,000 scientific works including peer-reviewed content from more than 116,000 scientists spanning 161 countries. Our authors range from globally-renowned Nobel Prize winners to up-and-coming researchers at the cutting edge of scientific discovery.
\n\n
In the same year that IntechOpen was founded, we launched what was at the time the first ever Open Access, peer-reviewed journal in its field: the International Journal of Advanced Robotic Systems (IJARS).
\n\n
The IntechOpen timeline
\n\n
2004
\n\n
\n\t
Intech Open is founded in Vienna, Austria, by Alex Lazinica and Vedran Kordic, two PhD students, and their first Open Access journals and books are published.
\n\t
Alex and Vedran launch the first Open Access, peer-reviewed robotics journal and IntechOpen’s flagship publication, the International Journal of Advanced Robotic Systems (IJARS).
\n
\n\n
2005
\n\n
\n\t
IntechOpen publishes its first Open Access book: Cutting Edge Robotics.
\n
\n\n
2006
\n\n
\n\t
IntechOpen publishes a special issue of IJARS, featuring contributions from NASA scientists regarding the Mars Exploration Rover missions.
\n
\n\n
2008
\n\n
\n\t
Downloads milestone: 200,000 downloads reached
\n
\n\n
2009
\n\n
\n\t
Publishing milestone: the first 100 Open Access STM books are published
\n
\n\n
2010
\n\n
\n\t
Downloads milestone: one million downloads reached
\n\t
IntechOpen expands its book publishing into a new field: medicine.
\n
\n\n
2011
\n\n
\n\t
Publishing milestone: More than five million downloads reached
\n\t
IntechOpen publishes 1996 Nobel Prize in Chemistry winner Harold W. Kroto’s “Strategies to Successfully Cross-Link Carbon Nanotubes”. Find it here.
\n\t
IntechOpen and TBI collaborate on a project to explore the changing needs of researchers and the evolving ways that they discover, publish and exchange information. The result is the survey “Author Attitudes Towards Open Access Publishing: A Market Research Program”.
\n\t
IntechOpen hosts SHOW - Share Open Access Worldwide; a series of lectures, debates, round-tables and events to bring people together in discussion of open source principles, intellectual property, content licensing innovations, remixed and shared culture and free knowledge.
\n
\n\n
2012
\n\n
\n\t
Publishing milestone: 10 million downloads reached
\n\t
IntechOpen holds Interact2012, a free series of workshops held by figureheads of the scientific community including Professor Hiroshi Ishiguro, director of the Intelligent Robotics Laboratory, who took the audience through some of the most impressive human-robot interactions observed in his lab.
\n
\n\n
2013
\n\n
\n\t
IntechOpen joins the Committee on Publication Ethics (COPE) as part of a commitment to guaranteeing the highest standards of publishing.
\n
\n\n
2014
\n\n
\n\t
IntechOpen turns 10, with more than 30 million downloads to date.
\n\t
IntechOpen appoints its first Regional Representatives - members of the team situated around the world dedicated to increasing the visibility of our authors’ published work within their local scientific communities.
\n
\n\n
2015
\n\n
\n\t
Downloads milestone: More than 70 million downloads reached, more than doubling since the previous year.
\n\t
Publishing milestone: IntechOpen publishes its 2,500th book and 40,000th Open Access chapter, reaching 20,000 citations in Thomson Reuters ISI Web of Science.
\n\t
40 IntechOpen authors are included in the top one per cent of the world’s most-cited researchers.
\n\t
Thomson Reuters’ ISI Web of Science Book Citation Index begins indexing IntechOpen’s books in its database.
\n
\n\n
2016
\n\n
\n\t
IntechOpen is identified as a world leader in Simba Information’s Open Access Book Publishing 2016-2020 report and forecast. IntechOpen came in as the world’s largest Open Access book publisher by title count.
\n
\n\n
2017
\n\n
\n\t
Downloads milestone: IntechOpen reaches more than 100 million downloads
\n\t
Publishing milestone: IntechOpen publishes its 3,000th Open Access book, making it the largest Open Access book collection in the world
\n
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The motor of the society is the industry and the research of this topic has to be empowered in order to increase and improve the quality of our lives.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/22.jpg",keywords:"Machine Learning, Intelligence Algorithms, Data Science, Artificial Intelligence, Applications on Applied Intelligence"},{id:"23",title:"Computational Neuroscience",scope:"Computational neuroscience focuses on biologically realistic abstractions and models validated and solved through computational simulations to understand principles for the development, structure, physiology, and ability of the nervous system. This topic is dedicated to biologically plausible descriptions and computational models - at various abstraction levels - of neurons and neural systems. This includes, but is not limited to: single-neuron modeling, sensory processing, motor control, memory, and synaptic plasticity, attention, identification, categorization, discrimination, learning, development, axonal patterning, guidance, neural architecture, behaviors, and dynamics of networks, cognition and the neuroscientific basis of consciousness. 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For example, some of the issues of interest could be the following: Advances in evolutionary computation (Genetic algorithms, Genetic programming, Bio-inspired metaheuristics, Hybrid metaheuristics, Parallel ECs); Applications of evolutionary algorithms (Machine learning and Data Mining with EAs, Search-Based Software Engineering, Scheduling, and Planning Applications, Smart Transport Applications, Applications to Games, Image Analysis, Signal Processing and Pattern Recognition, Applications to Sustainability).",coverUrl:"https://cdn.intechopen.com/series_topics/covers/25.jpg",keywords:"Genetic Algorithms, Genetic Programming, Evolutionary Programming, Evolution Strategies, Hybrid Algorithms, Bioinspired Metaheuristics, Ant Colony Optimization, Evolutionary Learning, Hyperparameter Optimization"},{id:"26",title:"Machine Learning and Data Mining",scope:"The scope of machine learning and data mining is immense and is growing every day. It has become a massive part of our daily lives, making predictions based on experience, making this a fascinating area that solves problems that otherwise would not be possible or easy to solve. This topic aims to encompass algorithms that learn from experience (supervised and unsupervised), improve their performance over time and enable machines to make data-driven decisions. It is not limited to any particular applications, but contributions are encouraged from all disciplines.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/26.jpg",keywords:"Intelligent Systems, Machine Learning, Data Science, Data Mining, Artificial Intelligence"},{id:"27",title:"Multi-Agent Systems",scope:"Multi-agent systems are recognised as a state of the art field in Artificial Intelligence studies, which is popular due to the usefulness in facilitation capabilities to handle real-world problem-solving in a distributed fashion. 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We welcome chapters presenting research on the many applications of multi-agent studies including, but not limited to, the following key areas: machine learning for multi-agent systems; modeling swarms robots and flocks of UAVs with multi-agent systems; decision science and multi-agent systems; software engineering for and with multi-agent systems; tools and technologies of multi-agent systems.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/27.jpg",keywords:"Collaborative Intelligence, Learning, Distributed Control System, Swarm Robotics, Decision Science, Software Engineering"}],annualVolumeBook:{},thematicCollection:[],selectedSeries:{title:"Artificial Intelligence",id:"14"},selectedSubseries:null},seriesLanding:{item:{id:"25",title:"Environmental Sciences",doi:"10.5772/intechopen.100362",issn:"2754-6713",scope:"
\r\n\tScientists have long researched to understand the environment and man’s place in it. The search for this knowledge grows in importance as rapid increases in population and economic development intensify humans’ stresses on ecosystems. Fortunately, rapid increases in multiple scientific areas are advancing our understanding of environmental sciences. Breakthroughs in computing, molecular biology, ecology, and sustainability science are enhancing our ability to utilize environmental sciences to address real-world problems. \r\n\tThe four topics of this book series - Pollution; Environmental Resilience and Management; Ecosystems and Biodiversity; and Water Science - will address important areas of advancement in the environmental sciences. They will represent an excellent initial grouping of published works on these critical topics.
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\r\n\tPollution is caused by a wide variety of human activities and occurs in diverse forms, for example biological, chemical, et cetera. In recent years, significant efforts have been made to ensure that the environment is clean, that rigorous rules are implemented, and old laws are updated to reduce the risks towards humans and ecosystems. However, rapid industrialization and the need for more cultivable sources or habitable lands, for an increasing population, as well as fewer alternatives for waste disposal, make the pollution control tasks more challenging. Therefore, this topic will focus on assessing and managing environmental pollution. It will cover various subjects, including risk assessment due to the pollution of ecosystems, transport and fate of pollutants, restoration or remediation of polluted matrices, and efforts towards sustainable solutions to minimize environmental pollution.
",annualVolume:11966,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/38.jpg",editor:{id:"110740",title:"Dr.",name:"Ismail M.M.",middleName:null,surname:"Rahman",fullName:"Ismail M.M. Rahman",profilePictureURL:"https://mts.intechopen.com/storage/users/110740/images/2319_n.jpg",institutionString:null,institution:{name:"Fukushima University",institutionURL:null,country:{name:"Japan"}}},editorTwo:{id:"201020",title:"Dr.",name:"Zinnat Ara",middleName:null,surname:"Begum",fullName:"Zinnat Ara Begum",profilePictureURL:"https://mts.intechopen.com/storage/users/201020/images/system/201020.jpeg",institutionString:null,institution:{name:"Fukushima University",institutionURL:null,country:{name:"Japan"}}},editorThree:null,editorialBoard:[{id:"252368",title:"Dr.",name:"Meng-Chuan",middleName:null,surname:"Ong",fullName:"Meng-Chuan Ong",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRVotQAG/Profile_Picture_2022-05-20T12:04:28.jpg",institutionString:null,institution:{name:"Universiti Malaysia Terengganu",institutionURL:null,country:{name:"Malaysia"}}},{id:"63465",title:"Prof.",name:"Mohamed Nageeb",middleName:null,surname:"Rashed",fullName:"Mohamed Nageeb Rashed",profilePictureURL:"https://mts.intechopen.com/storage/users/63465/images/system/63465.gif",institutionString:null,institution:{name:"Aswan University",institutionURL:null,country:{name:"Egypt"}}},{id:"187907",title:"Dr.",name:"Olga",middleName:null,surname:"Anne",fullName:"Olga Anne",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSBE5QAO/Profile_Picture_2022-04-07T09:42:13.png",institutionString:null,institution:{name:"Klaipeda State University of Applied Sciences",institutionURL:null,country:{name:"Lithuania"}}}]},{id:"39",title:"Environmental Resilience and Management",keywords:"Anthropic effects, Overexploitation, Biodiversity loss, Degradation, Inadequate Management, SDGs adequate practices",scope:"
\r\n\tThe environment is subject to severe anthropic effects. Among them are those associated with pollution, resource extraction and overexploitation, loss of biodiversity, soil degradation, disorderly land occupation and planning, and many others. These anthropic effects could potentially be caused by any inadequate management of the environment. However, ecosystems have a resilience that makes them react to disturbances which mitigate the negative effects. It is critical to understand how ecosystems, natural and anthropized, including urban environments, respond to actions that have a negative influence and how they are managed. It is also important to establish when the limits marked by the resilience and the breaking point are achieved and when no return is possible. The main focus for the chapters is to cover the subjects such as understanding how the environment resilience works, the mechanisms involved, and how to manage them in order to improve our interactions with the environment and promote the use of adequate management practices such as those outlined in the United Nations’ Sustainable Development Goals.
",annualVolume:11967,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/39.jpg",editor:{id:"137040",title:"Prof.",name:"Jose",middleName:null,surname:"Navarro-Pedreño",fullName:"Jose Navarro-Pedreño",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRAXrQAO/Profile_Picture_2022-03-09T15:50:19.jpg",institutionString:"Miguel Hernández University of Elche, Spain",institution:null},editorTwo:null,editorThree:null,editorialBoard:[{id:"177015",title:"Prof.",name:"Elke Jurandy",middleName:null,surname:"Bran Nogueira Cardoso",fullName:"Elke Jurandy Bran Nogueira Cardoso",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRGxzQAG/Profile_Picture_2022-03-25T08:32:33.jpg",institutionString:"Universidade de São Paulo, Brazil",institution:null},{id:"211260",title:"Dr.",name:"Sandra",middleName:null,surname:"Ricart",fullName:"Sandra Ricart",profilePictureURL:"https://mts.intechopen.com/storage/users/211260/images/system/211260.jpeg",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}}]},{id:"40",title:"Ecosystems and Biodiversity",keywords:"Ecosystems, Biodiversity, Fauna, Taxonomy, Invasive species, Destruction of habitats, Overexploitation of natural resources, Pollution, Global warming, Conservation of natural spaces, Bioremediation",scope:"
\r\n\tIn general, the harsher the environmental conditions in an ecosystem, the lower the biodiversity. Changes in the environment caused by human activity accelerate the impoverishment of biodiversity.
\r\n
\r\n\tBiodiversity refers to “the variability of living organisms from any source, including terrestrial, marine and other aquatic ecosystems and the ecological complexes of which they are part; it includes diversity within each species, between species, and that of ecosystems”.
\r\n
\r\n\tBiodiversity provides food security and constitutes a gene pool for biotechnology, especially in the field of agriculture and medicine, and promotes the development of ecotourism.
\r\n
\r\n\tCurrently, biologists admit that we are witnessing the first phases of the seventh mass extinction caused by human intervention. It is estimated that the current rate of extinction is between a hundred and a thousand times faster than it was when man first appeared. The disappearance of species is caused not only by an accelerated rate of extinction, but also by a decrease in the rate of emergence of new species as human activities degrade the natural environment. The conservation of biological diversity is "a common concern of humanity" and an integral part of the development process. Its objectives are “the conservation of biological diversity, the sustainable use of its components, and the fair and equitable sharing of the benefits resulting from the use of genetic resources”.
\r\n
\r\n\tThe following are the main causes of biodiversity loss:
\r\n
\r\n\t• The destruction of natural habitats to expand urban and agricultural areas and to obtain timber, minerals and other natural resources.
\r\n
\r\n\t• The introduction of alien species into a habitat, whether intentionally or unintentionally which has an impact on the fauna and flora of the area, and as a result, they are reduced or become extinct.
\r\n
\r\n\t• Pollution from industrial and agricultural products, which devastate the fauna and flora, especially those in fresh water.
\r\n
\r\n\t• Global warming, which is seen as a threat to biological diversity, and will become increasingly important in the future.
",annualVolume:11968,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/40.jpg",editor:{id:"209149",title:"Prof.",name:"Salustiano",middleName:null,surname:"Mato",fullName:"Salustiano Mato",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRLREQA4/Profile_Picture_2022-03-31T10:23:50.png",institutionString:null,institution:{name:"University of Vigo",institutionURL:null,country:{name:"Spain"}}},editorTwo:{id:"60498",title:"Prof.",name:"Josefina",middleName:null,surname:"Garrido",fullName:"Josefina Garrido",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRj1VQAS/Profile_Picture_2022-03-31T10:06:51.jpg",institutionString:null,institution:{name:"University of Vigo",institutionURL:null,country:{name:"Spain"}}},editorThree:{id:"464288",title:"Dr.",name:"Francisco",middleName:null,surname:"Ramil",fullName:"Francisco Ramil",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003RI7lHQAT/Profile_Picture_2022-03-31T10:15:35.png",institutionString:null,institution:{name:"University of Vigo",institutionURL:null,country:{name:"Spain"}}},editorialBoard:[{id:"220987",title:"Dr.",name:"António",middleName:"Onofre",surname:"Soares",fullName:"António Soares",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRNtzQAG/Profile_Picture_1644499672340",institutionString:null,institution:{name:"University of the Azores",institutionURL:null,country:{name:"Portugal"}}}]},{id:"41",title:"Water Science",keywords:"Water, Water resources, Freshwater, Hydrological processes, Utilization, Protection",scope:"
\r\n\tWater is not only a crucial substance needed for biological life on Earth, but it is also a basic requirement for the existence and development of the human society. Owing to the importance of water to life on Earth, early researchers conducted numerous studies and analyses on the liquid form of water from the perspectives of chemistry, physics, earth science, and biology, and concluded that Earth is a "water polo". Water covers approximately 71% of Earth's surface. However, 97.2% of this water is seawater, 21.5% is icebergs and glaciers, and only 0.65% is freshwater that can be used directly by humans. As a result, the amount of water reserves available for human consumption is limited. The development, utilization, and protection of freshwater resources has become the focus of water science research for the continued improvement of human livelihoods and society.
\r\n
\r\n\tWater exists as solid, liquid, and gas within Earth’s atmosphere, lithosphere, and biosphere. Liquid water is used for a variety of purposes besides drinking, including power generation, ecology, landscaping, and shipping. Because water is involved in various environmental hydrological processes as well as numerous aspects of the economy and human society, the study of various phenomena in the hydrosphere, the laws governing their occurrence and development, the relationship between the hydrosphere and other spheres of Earth, and the relationship between water and social development, are all part of water science. Knowledge systems for water science are improving continuously. Water science has become a specialized field concerned with the identification of its physical, chemical, and biological properties. In addition, it reveals the laws of water distribution, movement, and circulation, and proposes methods and tools for water development, utilization, planning, management, and protection. Currently, the field of water science covers research related to topics such as hydrology, water resources and water environment. It also includes research on water related issues such as safety, engineering, economy, law, culture, information, and education.
",annualVolume:11969,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/41.jpg",editor:{id:"349630",title:"Dr.",name:"Yizi",middleName:null,surname:"Shang",fullName:"Yizi Shang",profilePictureURL:"https://mts.intechopen.com/storage/users/349630/images/system/349630.jpg",institutionString:"China Institute of Water Resources and Hydropower Research",institution:{name:"China Institute of Water Resources and Hydropower Research",institutionURL:null,country:{name:"China"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"216491",title:"Dr.",name:"Charalampos",middleName:null,surname:"Skoulikaris",fullName:"Charalampos Skoulikaris",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRMsbQAG/Profile_Picture_2022-04-21T09:31:55.jpg",institutionString:null,institution:{name:"Aristotle University of Thessaloniki",institutionURL:null,country:{name:"Greece"}}},{id:"300124",title:"Prof.",name:"Thomas",middleName:null,surname:"Shahady",fullName:"Thomas Shahady",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002kuIgmQAE/Profile_Picture_2022-03-18T07:32:10.jpg",institutionString:null,institution:{name:"Lynchburg College",institutionURL:null,country:{name:"United States of America"}}}]}]}},libraryRecommendation:{success:null,errors:{},institutions:[]},route:{name:"chapter.detail",path:"/chapters/77622",hash:"",query:{},params:{id:"77622"},fullPath:"/chapters/77622",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()