Introductory Chapter: Mitochondrial Diseases - Advances and Perspectives - My Point of View

1. Introduction

There is only one metabolic pathway that is under the dual control of the mitochondrial genome (mtDNA) and the nuclear genome (nDNA). Disorders in the mitochondrial respiratory chain are called by convention “mitochondrial diseases.” Mitochondrial disorders symbolize a major challenge in medicine. Much of the mitochondrial proteins are encoded by nuclear DNA (nDNA), while only a few are encoded by mitochondrial DNA (mtDNA). Mutations in mtDNA or mitochondrial-related nDNA genes can cause a mitochondrial disorder. The disorder can affect multiple organs in different locations and severity; but there are some ways that involve only one organ. Modifications of the mitochondrial oxidative phosphorylation system can generate mutations in both mitochondrial DNA and nuclear DNA that lead to mitochondrial diseases. Mitochondrial diseases comprise a diverse group of genetic disorders, which appear at any age and have a wide spectrum of clinical symptoms. This leads to highly changeable cases, making it difficult to diagnose mitochondrial diseases. The latest advances in genetic testing and original reproductive options hold great promise for improving the clinical recognition and treatment of mitochondrial diseases. In this chapter we discuss developments in the recognition and diagnosis of mitochondrial diseases. In the last five decades, the effect of mitochondrial diseases on biological systems began to be widely investigated. This chapter explains the most important aspects in our opinion of mitochondrial diseases.

2. Brief history of mitochondria

The generation of adenosine triphosphate by oxidative phosphorylation occurs in the mitochondria; about 90% of the cell’s energy need is satisfied during the hydrolysis of ATP produced in this way. In addition, mitochondria are also involved in other processes including, but not limited to, the formation of iron and sulfur groups, the citric acid cycle, the regulation of apoptosis1, and calcium homeostasis in conjunction with the endoplasmic reticulum.

Mitochondria do not have nearly the amount of DNA necessary to encode all the specific proteins of mitochondria; however, millions of years of evolution could explain a progressive loss of autonomy. The endosymbiotic hypothesis could be called a theory, but no experimental reason can be offered to test it. Only indirect confirmation can be accessed in support of the proposal, which is the most likely justification for the mitochondria starting point. The verification necessary to change the model from hypothesis to theory is probably forever lacking in ancient times.

3. Mitochondrial diseases

Studies of genetic pathologies that affect mitochondrial metabolism as a consequence of modifications in genes encoded by mitochondrial DNA or genes encoded by nuclear DNA for dynamic proteins inside the mitochondria began in 1988. Since that year, a new notional “mitochondrial genetics” has become visible; based on three attributes of mtDNA: (1) polyplasmy; (2) maternal inheritance; and (3) mitotic segregation. Diagnosis of mtDNA-connected diseases was completed through genetic analysis and experimental advances that incorporated histochemical staining of muscle or brain sections, single-fiber polymerase chain reaction (PCR) of mtDNA, and the design of a “hybrid” Immortal (cytoplasmic hybrid) derivative from patient fibroblast cell lines.

4. My participation in studies with mitochondria

In the last three decades, our laboratory has investigated the lipid peroxidation of biological membranes of various tissues and different species, as well as liposomes prepared with phospholipids with a high content of polyunsaturated fatty acids. We analyzed the effect of various antioxidants such as alpha tocopherol, vitamin A, melatonin and its structural analogues and conjugated linoleic acid, among others [1, 2]. The integrity of the mitochondrial membranes and the function of numerous protein complexes in the ETC [3] are determined by cardiolipin, which is a unique class of specific mitochondrial phospholipids that exist almost exclusively in the inner membrane of mitochondria (IMM). In most mammalian tissues, tetralinoleoylcardiolipin (L4CL) is the main form of cardiolipins, this molecule contains four chains of structural linoleic acid. The incorporation of four LA side chains into L4CL and their presence in mitochondria allow L4CL to be easily oxidized by reactive oxygen species and then to generate an electrophilic reaction Figure 1 [4].

Figure 1.

Chemical mechanisms for 4-HNE formation from lipid peroxidation. (A) General scheme for the formation of 4-HNE from decomposition of lipid hydroperoxides that can be generated from free radical oxidation of ω-6 PUFA or enzymatic oxidation by lipoxygenases. (B) Lipid electrophiles generated from oxidation of mitochondrial cardiolipin: Oxidation of L₄CL by the peroxidase activity of cyt c and CL complex in the presence of H₂O₂ results in the formation of hydroperoxyoctadecadienoic acid (HpODE), 9-HpODE-CL and 13-HpODE-CL. During this process, through intra-molecular peroxyl radical addition and decomposition of an unstable intermediate, several reactive aldehydes are produced including epoxyalcohol-aldehyde-CL (EAA-CL), 4-HNE, and 4-oxo-2-nonenal (4-ONE). Reproduced from Redox Biol. 2015 Apr; 4: 193–199. Rights Managed by Elsevier.

5. Conclusions

Aging and age-related diseases have been connected with mitochondrial uncoupling and elevated ROS formation. Dysfunctional mitochondria incline to modified lipid metabolism and augmented lipid peroxidation products. Mitochondrial antioxidants that can re-establish function and prevent pathological lipid peroxidation are showing guarantee in diminishing biological aging and therefore they may offer advantage for slowing the development to age-related diseases such as neurodegeneration. In parallel, novel drug groups are providing a unusual strategy to delay aging during elimination of senescent cells. By mean of these drugs as instruments offer a chance to amplify our understanding of whether the alterations in reactive oxygen species, lipid metabolism and mitochondrial lipids detected during aging and diseases are due to the increase of senescent cells.

6. General remarks, and perspectives

It has been fascinating to follow the field of mitochondrial diseases research during almost five decades. From my experience, it is impossible to predict which aspects in this area of research will dominate in the future.

Acknowledgments

The author is grateful to his mentors: Rodolfo Brenner and Phillip Strittmatter, all his Ph.D. students, and post docs.