InTechOpen uses cookies to offer you the best online experience. By continuing to use our site, you agree to our Privacy Policy.

Biochemistry, Genetics and Molecular Biology » "Gene Expression and Regulation in Mammalian Cells - Transcription Toward the Establishment of Novel Therapeutics", book edited by Fumiaki Uchiumi, ISBN 978-953-51-3868-6, Print ISBN 978-953-51-3867-9, Published: February 28, 2018 under CC BY 3.0 license. © The Author(s).

Chapter 8

Changes in the Expression and the Role of Sirtuin 3 in Cancer Cells and in Cardiovascular Health and Disease

By Ozkan Ozden and Kevser Tural
DOI: 10.5772/intechopen.71865

Article top


Changes in the expression of p53, signal transduction pathway, and insulin-lipoprotein-cholesterol genes in SIRT3-deficient livers compared to SIRT3 wild-type mouse based on [66].
Figure 1. Changes in the expression of p53, signal transduction pathway, and insulin-lipoprotein-cholesterol genes in SIRT3-deficient livers compared to SIRT3 wild-type mouse based on [66].

Changes in the Expression and the Role of Sirtuin 3 in Cancer Cells and in Cardiovascular Health and Disease

Ozkan Ozden1 and Kevser Tural2
Show details


Sirtuin 3, an NAD+-dependent deacetylase, whose expression is considered a marker in life extension, is downregulated with age and in various diseases. Sirtuin 3 is predominantly localized to the mitochondria and considered a fidelity protein for the integrity and function of this organelle. Some studies report its localization in the nucleus to regulate the expression of stress response–related genes and that reduced expression of SIRT3 produces a cellular milieu permissive for human pathologies. Since the expression and activity of Sirtuin 3 are important for the regulation of antioxidant defense, metabolism, and apoptosis initiation, the expression of SIRT3 is also important in the context of age-associated illnesses. A variety of small molecules are being developed to modulate the expression or activity of Sirtuin 3 and are potentially a valuable strategy to change mitochondrial acetylome to treat several diseases. The AMPK-PGC1α-SIRT3 axis plays a critical role in preserving mitochondrial biogenesis and function. Here, we summarize how changes in Sirtuin 3 expression are regulated in cancer and dysfunctions in cardiovascular diseases. The potential therapeutic strategies by targeting Sirtuin 3 expression to improve mitochondrial function in cancer and cardiovascular diseases are summarized.

Keywords: sirtuin, SIRT3 expression, cancer, cardiovascular diseases, stress

1. Introduction

With the identification of sirtuins (SIRTs), acetylation/deacetylation of proteins has become evident as an essential and highly regulated posttranslational modification, especially for the majority of mitochondrial proteins [1]. Acetylation can regulate the activity of an enzyme, stability or subcellular localization of a protein, transcriptional activity, and DNA-protein interactions. Silent information regulator 2 (Sir2) is the founding member of sirtuins, which was characterized in yeast, Saccharomyces cerevisiae. Sir2 functions in silencing gene expression by histone deacetylation [2]. It has been proposed that overexpression of Sir2 leads to an increase in life expectancy in yeast and other model organisms, such as Caenorhabditis elegans and Drosophila [3]. In these model organisms, the activity of Sir2 is stimulated by multiple physiological events and stress signals, including starvation, calorie restriction, osmotic stress, and heat shock [4, 5].

SIRT histone deacetylases differ from traditional class I and II histone deacetylases (HDACs) in two ways: first, the substrates of SIRTs are not limited to histones and they can target key enzymes or proteins in the cytoplasm and mitochondria in addition to histones in the nucleus [6]. Second, SIRTs require nicotinamide adenine dinucleotide (NAD+) for their enzymatic activity. Their dependence on NAD+ is important for the regulation of metabolism and links the activity of SIRTs to the energy status of the cells. This is important for a cell to respond to different stress factors with a suitable stress response to sustain homeostasis. For example, in starvation, calorie restriction, exercise, or a cellular genotoxicity, increased cellular NAD+ levels can activate SIRTs. Like Sir2, activated and/or upregulated SIRTs deacetylate their numerous targets to create a proper cellular stress response.

In mammals, seven SIRT isoforms have been identified, which can be found in different subcellular compartments. SIRT1, SIRT6, and SIRT7 are localized to the nucleus; SIRT3, SIRT4, and SIRT5 are localized mainly in the mitochondria; and SIRT2 is mostly present in the cytoplasm, but it might translocate into the nucleus [7]. Mammalian SIRTs have been proposed to have numerous beneficial effects, such as increasing insulin secretion, ATP synthesis, and lipid mobilization; however, the mechanism of how these beneficial effects translate into life span extension is poorly understood. SIRT3 gene expression has been observed to be upregulated with high frequency in long-lived individuals [8, 9]. In these individuals, mutations in an enhancer region of the SIRT3 gene are believed to upregulate its expression, and high SIRT3 expression can be considered a marker for longevity.

Calorie restriction is defined as lowering dietary calorie intake without malnutrition and has been described to extend the life span of many organisms from yeast to mammals and decrease the occurrence of age-related diseases, such as cancer, cardiovascular diseases, neurodegenerative diseases, and diabetes [10, 11]. In both yeast and C. elegans, caloric restriction–induced longevity is reliant on the existence of Sir2 [4]. Parallel to studies on Sir2, subsequent studies suggested that beneficial effects of calorie restriction might be associated with the upregulation of SIRT expression. SIRT3 transcription was stimulated in hepatocytes and skeletal muscle of mice on calorie restricted–diet, while a long-term high-fat diet resulted in lowering SIRT3 expression and increasing mitochondrial protein acetylation [12, 13]. SIRT3 expression declines in individuals over 59 years of age [14, 15], which may contribute to the increased incidence of cardiovascular diseases and cancer in aging population. Studying SIRT3 in these diseases may provide important mechanistic connection between the mitochondrial function and age-associated disorders [16, 17, 18, 19, 20]. SIRT3 expression is important for mitochondrial biogenesis, regulation of metabolism, ATP synthesis, suppression of reactive oxygen species (ROS), stress responses, and cell signaling [15, 19, 21, 22, 23].

Investigators report that SIRT3 regulates the activity of the transcription factors, Forkhead box O 3a (FOXO3a), and nuclear factor κB (NF-κB) [24, 25]; however, regulation of SIRT3 transcription itself is not completely understood up-to-date. SIRT3 gene is located in a bidirectional arrangement with another gene, called PSMD13, in a phylogenetically conserved manner. The promoter of the two genes is separated by a 788-bp intergenic region. SIRT3 holds a rich GC content but lacks a TATA box. Human SIRT3 promoter has binding sites for activator protein (AP-1), NF-κB, ZF5 transcription factor, GATAs, and specificity protein 1 (SP1) [26]. There is evidence that peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) upregulates SIRT3 transcription, conveyed by an estrogen-related receptor (ERR)-binding element in the promoter of SIRT3 in mouse muscle cells and hepatocytes [27]. PGC-1α and ERRα display a synergic action on SIRT3 promoter activity [27]. Furthermore, SIRT3 increases PGC1-α gene expression by activating AMPK signaling pathway and provides a positive feedback loop. Activation of AMPK signaling pathway leads to phosphorylation of cAMP response element-binding protein (CREB), which directly activates the PGC1-α promoter [28]. The positive feedback loop between SIRT3 and PGC1-α is important for mitochondrial biogenesis and activation of enzymes associated with the antioxidant system and regulation of metabolism [6, 27, 28]. In another study, bioinformatics analysis has been revealed that transcription factor binding motifs might be present in SIRT3 promoter. Nuclear respiratory factor 2 (NRF-2) transcription factor regulates mitochondrial genes, including antioxidant enzymes. NRF-2 has been reported to directly bind to the SIRT3 promoter and increase the expression of SIRT3 mRNA during nutrient stress [29].

2. Changes in Sirtuin 3 expression in carcinogenesis

Acetylation/deacetylation of specific lysine amino acids of proteins is a prevalent regulatory mechanism responsible for modulating signaling pathways, survival, apoptosis, and energy metabolism that takes part in important roles in cellular transformation [30]. SIRTs regulate various cellular activities, such as gene silencing, cellular proliferation, survival, apoptosis, stress response, and energy generation by protein deacetylation [31, 32].

SIRT3 is mostly localized in the mitochondria, and it deacetylates many critical metabolism-related proteins; decreases the levels of mitochondrial ROS; and ultimately regulates proliferation, differentiation, and survival in response to a stress stimulus [20, 33]. SIRT3 is considered a fidelity protein because it plays important roles in integrity and maintenance of mitochondrial function [6, 34, 35]. SIRT3 expression has been determined to be the highest in the heart, liver, brain, and brown adipose tissue where metabolic activity is relatively high [36]. Genetic deletion of SIRT3 in mouse has been reported not to produce any significant phenotypic abnormalities when the mouse is younger than 1 year old. SIRT3 knockout mice are viable, fertile, and metabolically active when these animals are still young. The difference between SIRT3-deficient mice and wild-type animals is that knockout mice express increased numbers of hyperacetylated proteins in their mitochondria, suggesting SIRT3 is the primary deacetylase in this organelle [37]. In normal conditions, SIRT3 gene deficiency does not produce any abnormalities; however, a different picture emerges when SIRT3 knockout mice get older than 12 months or encounter a stress stimulus. These mice might be prone to tumor formation, especially in the breast [38].

SIRT3-deficient mice older than 1 year old develop well-differentiated estrogen- and progesterone-positive mammary tumors [38]. This subtype of mammary tumors is more commonly observed in women over 60 years old. In human estrogen- and progesterone-positive mammary tumor samples, SIRT3 expression is found to be reduced compared to noncancerous breast tissues [38]. The SIRT3 knockout mouse is suggested to be a convenient model to study this subtype of breast tumors. Additional studies on SIRT3-deficient mice revealed that ionizing radiation causes vacuolization in SIRT3 knockout mouse hepatocytes, suggesting SIRT3 protects hepatocytes against ionizing radiation–induced damage [38]. Moreover, SIRT3-deficient mice may develop age-related hearing loss [19]. SIRT3 expression is reduced in various tumors, and at least one allele of SIRT3 gene is deleted in about 40% of breast and ovarian tumors and 20% of all human cancer samples [38, 39]. SIRT3 expression is associated closely with cancer because it has essential regulatory roles in mitochondrial ROS scavenging, ATP synthesis, metabolism, and mitochondrial function [38].

Electron transport chain in mitochondria is the main source of the generation of ROS, such as superoxide. ROS homeostasis is strictly regulated in the cell, and while ROS play a part as secondary messengers at normal conditions, excessive ROS can damage cellular biomolecules and contribute to mitochondrial dysfunction and carcinogenesis [40]. SIRT3 has been shown to directly deacetylate and stimulate manganese superoxide dismutase (MnSOD) activity, which is the principle ROS scavenger in the mitochondria [20]. In addition, SIRT3 could induce expression of MnSOD, catalase, and isocitrate dehydrogenase (IDH2) by deacetylating FOXO3a transcription factor, triggering its translocation into the nucleus and transcription of these antioxidant enzymes [20, 25, 41, 42].

In the majority of tumors, pyruvate is preferentially transformed into lactate even in the existence of adequate oxygen. In this process, termed the Warburg effect, metabolism shifts in favor of glycolysis to increase the raw materials necessary for making new cancer cells [30, 43, 44]. In other words, glycolytic rate is increased in cancer cells. SIRT3 has been revealed to bring about degradation of HIF-1α, which results in suppression of the expression genes involved in glycolysis and angiogenesis [45]. SIRT3 displays this action indirectly through reductions in ROS level, which activates oxygen-dependent prolyl hydroxylases (PHD). In this regard, profilin1 (Pfn1) has been reported to have an anticancer feature in pancreatic cancer by upregulating SIRT3, which in turn results in degradation of HIF-1α and reduction in the expression of glycolytic genes [46]. Furthermore, SIRT3 has a second action to stimulate mitochondrial respiration by directly targeting electron transport chain and some metabolic enzymes, such as pyruvate dehydrogenase complex, and induce higher ATP production [22, 47, 48, 49].

Since SIRT3 takes part in mitochondrial ROS scavenging, regulation of metabolism, and mitochondrial function, it is not surprising that reduced expression of SIRT3 is highly associated with carcinogenesis [6, 30]. In addition, reduced SIRT3 expression is suggested to be a biomarker for breast cancer associated with poor prognosis [50, 51]. In addition to breast cancer, SIRT3 might play tumor suppressive roles in pancreatic cancer [52], hepatocellular carcinoma [53, 54], B cell lymphoma cells [55], and metastatic ovarian cancer [56]. In addition, kaempferol, a flavonoid, increases SIRT3 expression and its mitochondrial import; hence, it stimulates apoptosis in leukemia cell lines [57].

SIRT3 has also been reported to take part in an oncogenic function by promoting cancer initiation or progression depending on the tissue of origin and intracellular signal pathways [30]. Oncogenic properties of SIRT3 are attributed to its actions in stimulation of proliferation, resistance to oxidative stress, and suppression of apoptosis. SIRT3 could play an oncogenic role in a spectrum of cancers including oral squamous cell carcinoma [58], breast cancer [59], esophageal cancer [60], gastric cancer [61], colorectal cancer [62], and melanoma cell lines [63].

SIRT3 is predominantly located in the mitochondria; however, there are studies reporting its localization in the nucleus and having a function in regulating gene expression response to stress factors [64, 65]. We have previously shown that the loss of expression of SIRT3 in mouse liver and cultured mouse embryonic fibroblasts results in a cellular environment susceptible to carcinogenesis and cellular transformation [38, 66]. In the subsequent study, we investigated how SIRT3 alters the gene expression of cancer-related pathways in SIRT3 wild-type and SIRT3 knockout mouse hepatocytes. We studied how deficiency of SIRT3 expression might change the gene expression profile of various transcription factors and proteins linked to tumor formation in addition to genes associated with metabolism using a commercially available real-time polymerase chain reaction kit that screens gene expression profiling of diverse pathways [66]. We found upregulated expression of several genes having oncogenic properties including cyclin-dependent kinase inhibitor 1A P21 (Cdkn1a), myelocytomatosis oncogene (Myc), and nitric oxide synthase (NOS2) in SIRT3-deficient mouse liver. These genes are often overexpressed in human cancers, primarily in breast tumors. In contrast, several genes that were previously reported to be downregulated in human breast cancer containing B-cell translocation gene 2 (BTG2), early growth response 1 (EGR1), and Gadd4 had decreased expression with larger than 2-folds in the SIRT3-deficient hepatocytes [66]. The list of genes with larger than 2-folds in the cancer-associated pathways and genes associated with insulin-lipoprotein-cholesterol metabolism is presented in Figure 1 .


Figure 1.

Changes in the expression of p53, signal transduction pathway, and insulin-lipoprotein-cholesterol genes in SIRT3-deficient livers compared to SIRT3 wild-type mouse based on [66].

3. Protective effects of SIRT3 in stress responses in the heart and changes in SIRT3 expression in cardiovascular diseases

The heart produces and uses more than 90% of its ATP from mitochondrial aerobic respiration in the cardiomyocytes, which have one of the highest mitochondrial density among all mammalian cells [67]. Mitochondria are critical in regulating oxidative stress signaling during cardiovascular physiology and pathology by regulating cell death, ROS homeostasis, and ATP levels in cardiomyocytes. Heart failure might be caused by the imbalance in cardiac metabolism, oxidative stress, and opening of the mitochondrial permeability transition pore, which are important cellular contributors to myocardial ischemia/reperfusion (IR) injury and the development of cardiac hypertrophy [68, 69, 70]. Recent evidence demonstrated that the mitochondrial NAD+-dependent enzyme, SIRT3, may regulate critical intracellular processes, such as oxidative stress, cell survival, and cellular metabolism for a healthy cardiac function [71].

In mammals, SIRT3 is one of seven NAD+-dependent protein deacetylases or ADP-ribosyltransferases that regulates mitochondrial enzyme activity important in maintaining the integrity of the mitochondria and having a cardioprotective role [17, 72, 73]. Lanza et al. found that SIRT3 expression is downregulated with age, especially pronounced after 60 years old, and chronic endurance training causes elevation of SIRT3 expression along with beneficial health effects and potential lifespan-extending properties [74]. SIRT3, whose expression is rich in the heart, is the main deacetylase in the mitochondria and its absence produces hyperacetylation of numerous proteins in this organelle [75]. Increased acetylation of mitochondrial proteins, such as cyclophilin D, an important regulator of the permeability transition pore (mPTP), in the heart in response to IR injury has been reported [69, 76].

The changes in expression of SIRT3 are appealing to the study of cardiovascular diseases because of its presence mainly in the mitochondria, where a large part of the reactive oxygen species (ROS) is generated in the cardiomyocytes [77]. Overproduction of ROS in mitochondria has been linked to the development of cardiac hypertrophy [71]. High levels of cellular ROS damage biomolecules and accelerate the death of cardiomyocytes via apoptosis and necrosis [78, 79, 80, 81]. Increased ROS was measured in cardiomyocytes isolated from hearts with hypertrophy induced by α-adrenergic agonists, namely angiotensin II, endothelin 1, norepinephrine, tumor necrosis factor, or cyclic mechanical stretch. Furthermore, induced hypertrophy could be repressed by the application of antioxidants [82, 83, 84]. ROS generation has been shown to activate diverse hypertrophic signal transduction pathways, including NF-κB, mitogen-activated protein kinase (MAPK), and protein kinase C (PKC) to stimulate hypertrophy [85, 86, 87]. SIRT3 mediates the mitochondrial ROS levels by inducing transcriptional expression of mitochondrial antioxidant enzymes by deacetylating FOXO3a transcription factor and its translocation into the nucleus [42]. In other words, SIRT3 has been well shown to participate in preventing hypertrophy by restricting ROS through activating MnSOD and catalase.

SIRT3 knockout mice are born without any significant abnormalities in their hearts; however, as they become 2 months of age, they display some indications of cardiac hypertrophic response and interstitial fibrosis, suggesting a protective role of SIRT3 against cardiac hypertrophy [42]. SIRT3 gene–removed mice have been reported to develop an accelerated age-related weakening in cardiac contractile function, which is characterized as an increase in end-diastolic volume, and are more prone to transaortic constriction-induced left ventricular hypertrophy [68, 88]. SIRT3 gene–removed mice can also display spontaneous pulmonary hypertension and have reduced oxygen consumption rate in their pulmonary artery smooth muscle cells [89]. In those knockout cells, the investigators pointed out that the expression of HIF1α, STAT3, and NFATc2 transcription factors increased, which might be responsible for the development of this disease [89]. Knockdown of SIRT3 expression increases the vulnerability of both H9c2 cardiomyocytes and Langendorff preparations to simulate IR injury [18]. Moreover, IR injury is more pronounced in the aged hearts where SIRT3 expression is reduced, suggesting SIRT3 deficiency contributes to age-related loss of resistance to IR injury [18]. Consistently, exposure of SIRT3-deficient mouse hearts to global IR using a Langendorff-mode perfusion leads to significantly reduced postischemic recovery of cardiac function relative to wild-type mouse hearts due to both elevated mitochondrial ROS production and protein oxidation [90]. Expression of SIRT3 is upregulated in response to stress and its overexpression has a protective role for cardiomyocytes from stress-mediated cell death by deacetylating Ku70 and preventing translocation of BAX to mitochondria [91]. Additionally, SIRT3 overexpression protects cardiomyocytes from oxidative stress by downregulating apoptosis regulator BAX and BCL-2 by inducing NF-κB transcription factor [24].

SIRT3 also has crucial roles in regulating metabolism of cardiovascular cells. SIRT3 improves mitochondrial oxidative phosphorylation for the production of ATP [47]. SIRT3 also regulates lipid metabolism by directly activating long-chain acyl CoA dehydrogenase (LCAD) enzyme activity, which diminishes lipid accumulation–induced cardiac hypertrophy [92]. In this regard, SIRT3 expression is downregulated in mice fed with high-fat diet; correspondingly, SIRT3 gene–removed mouse heart displays more noticeable hypertrophy [93]. Heart isolated from SIRT3-deficient mice shows impaired mitochondrial and cardiac contractile function accompanied by increased glycolysis and decreased palmitate oxidation and oxygen consumption [88]. Additionally, in SIRT3-deficient heart cells, 84 hyperacetylated mitochondrial proteins including enzymes for fatty acid metabolism, several subunits of electron transport chain, and enzymes involved in the Krebs cycle have been identified, proposing the importance of SIRT3 in maintaining a stable myocardial energy status [88].

Exogenous SIRT3 expression decreases mitochondrial ROS production and improves respiratory capacity in vitro [94, 95]. In recent years, increasing numbers of pharmacological agents to stimulate the expression or activity of SIRT3 to support a healthy cardiac function have been reported. Resveratrol, which is a general SIRT activator, is proposed to have a cardioprotective effect by decreasing the levels of mitochondrial ROS through upregulation of SIRT3 expression [96]. Resveratrol activates AMPK-PGC-1α, which activates the binding of ERRα to the SIRT3 promoter and increases SIRT3 mRNA transcription. Increased SIRT3 expression in the mitochondria in turn increases the deacetylation and activation of antioxidant enzymes, primarily MnSOD, and stimulates ATP synthesis to contribute to reduction in oxidative injury in endothelial cells [96]. In a recent study, it has been reported that adjudin, which is a lonidamine analog, upregulated the expression of SIRT3 and consequently protected cells against oxidative damage by eliminating ROS [97]. This agent might also have a cardioprotective potential.

In addition to resveratrol, other agents use the same signaling pathway to support cardioprotection. Melatonin has been reported to have an important cardioprotective action, which also uses AMPK-PGC-1α-SIRT3 signaling pathway. The investigators of the study reported that the protective effect of melatonin on diabetic myocardial IR injury is prevented by silencing SIRT3 expression [98].

Honokiol, which is a polyphenol derived from magnolia tree, lessens cardiac hypertrophy and fibrosis by activating SIRT3 and protects cardiomyocytes from doxorubicin-induced cell destruction and death by promoting mitochondrial fusion and limiting mitochondrial ROS levels and mtDNA damage [99, 100]. Adenovirus-mediated overexpression of SIRT3 might decrease pathogenesis of cardiovascular diseases by inhibition of Dox-induced cardiac hypertrophy and mitochondrial defects. Overexpression of the transcriptional cofactor receptor-interacting protein 140 (RIP140) increased cardiomyocyte hypertrophy and decreased ATP production along with mitochondrial dysfunction by decreasing the expression of SIRT3 in neonatal rat cardiomyocytes [101]. Repression of SIRT3 expression by RIP140 is dependent on ERRα [101]. A hexokinase inhibitor, 2-deoxy-d-glucose, administration significantly improves cardiac function and reduces myocardial apoptosis [102]. Zhen et al. pointed out that upregulation of SIRT3 expression along with SIRT1 by this agent might be important contributors to its protective action against septic cardiomyopathy [102]. Stimulation of SIRT3 expression improves the mitochondrial respiratory function and improves the cardiac function of mice. Metformin, which is a drug used for the treatment of diabetes, upregulates the expression of SIRT3 in about 8 weeks old mice with heart failure after myocardial infarction [103]. It was suggested that metformin-mediated SIRT3 upregulation and deacetylation of PGC-1α increase mitochondrial ATP production and mitochondrial oxygen consumption rates in the mouse hearts of myocardial infarction and decrease the associated damage [103]. A summary of agents to stimulate the expression of SIRT3 to support a healthy cardiac function and the possible targets of SIRT3 is presented in Table 1 .

SIRT3 stimulating potential cardioprotective agentsUpstream signaling of SIRT3Direct or indirect SIRT3 substrates and targetsPotential effects of agents in cardiovascular system and cardiomyocytesAssociated references
ResveratrolAMPK, PGC-1α, and ERRαMnSOD, IDH2, GSH-Px, FOXO3aScavenges mtROS[96]
MelatoninAMPK and PGC1αMnSOD, NRF1, TFAM, cytochrome cScavenges mtROS, stimulates mitochondrial biogenesis, and reduces apoptosis[98]
HonokiolN/AMnSOD, OGG1, MFN1, OPA1, Ku70, BCL-2, BAX, NF-κBScavenges mtROS, reduces apoptosis, and enhances mitochondrial fusion[24, 91, 100]
2-deoxy-d-glucoseN/ABAX, BAKReduces apoptosis[24, 102]
MetforminN/APGC-1αStimulates mitochondrial ATP production and oxygen consumption rates[103]
AdjudinN/AIDH2Scavenges mtROS[96, 97]
RIP140 (SIRT3 repressing TF)ERRαLCADIncreases mtROS and lipid accumulation[92, 101]

Table 1.

Various agents to stimulate the expression of SIRT3 and the cardioprotective actions of SIRT3.

MnSOD: manganese superoxide dismutase; IDH2: isocitrate dehydrogenase; Forkhead box O 3a (FOXO3a); LCAD: long-chain acyl-CoA dehydrogenase; AMPK: AMP-activated protein kinase; GSH-Px: glutathione peroxidase; PGC-1α: peroxisome proliferator-activated receptor gamma coactivator 1-alpha; ERRα: estrogen-related receptor alpha; NRF1: nuclear respiratory factor 1; TFAM: transcription factor A, mitochondrial; OGG1: 8-oxoguanine glycosylase; MFN-1: mitofusin-1; OPA1: dynamin-like 120 kDa protein; Ku70; ATP-dependent DNA helicase II, 70 kDa subunit; BCL-2: B-cell lymphoma 2; NF-κB: nuclear factor kappa-light-chain enhancer of activated B cells; TF: transcription factor.

4. Conclusions

Cardiovascular diseases and cancer are most common causes of age-associated death around the world. SIRT3 has been shown to have essential roles in aging, longevity, and stress response since reduced expression or loss of function of SIRT3 brings about an intracellular milieu permissive for age-related illnesses. The mechanisms of how SIRT3 protects cells against cancer formation or cardiovascular diseases are not well understood because of the fact that SIRT3 has several targets or interacting partners in diverse pathways. Beneficial possessions of SIRT3 on cancer and particularly on various cardiovascular diseases have been reported; however, translating the modulation of SIRT3 expression using small molecules for clinical benefit is in its initial stages. Identification of agents to target SIRT3 expression to improve mitochondrial function will harvest new therapeutic strategies in the treatment of cancer and cardiovascular diseases.


We thank Dr. Nancy Krett and Dr. Barbara Jung for helpful reading of the manuscript.


1 - Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, et al. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science. 2009;325:834-840. DOI: 10.1126/science.1175371
2 - Guarente L, Kenyon C. Genetic pathways that regulate ageing in model organisms. Nature. 2000;408:255-262. DOI: 10.1038/35041700
3 - Kaeberlein M, McVey M, Guarente L. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes & Development. 1999;13:2570-2580
4 - Lin SJ, Defossez PA, Guarente L. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science. 2000;289:2126-2128
5 - Wood JG, Rogina B, Lavu S, Howitz K, Helfand SL, Tatar M, et al. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature. 2004;430:686-689. DOI: 10.1038/nature02789
6 - Torrens-Mas M, Oliver J, Roca P, Sastre-Serra J. SIRT3: Oncogene and tumor suppressor in cancer. Cancers (Basel). 2017;9. DOI: 10.3390/cancers9070090
7 - Frye RA. Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochemical and Biophysical Research Communications. 2000;273:793-798. DOI: 10.1006/bbrc.2000.3000
8 - Bellizzi D, Rose G, Cavalcante P, Covello G, Dato S, De Rango F, et al. A novel VNTR enhancer within the SIRT3 gene, a human homologue of SIR2, is associated with survival at oldest ages. Genomics. 2005;85:258-263. DOI: 10.1016/j.ygeno.2004.11.003
9 - Rose G, Dato S, Altomare K, Bellizzi D, Garasto S, Greco V, et al. Variability of the SIRT3 gene, human silent information regulator Sir2 homologue, and survivorship in the elderly. Experimental Gerontology. 2003;38:1065-1070
10 - McCay CM, Crowell MF, Maynard LA. The effect of retarded growth upon the length of life span and upon the ultimate body size. Nutrition. 1989;5:155-171 discussion 72. 1935
11 - Weindruch R, Walford RL, Fligiel S, Guthrie D. The retardation of aging in mice by dietary restriction: Longevity, cancer, immunity and lifetime energy intake. The Journal of Nutrition. 1986;116:641-654
12 - Hirschey MD, Shimazu T, Jing E, Grueter CA, Collins AM, Aouizerat B, et al. SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome. Molecular Cell. 2011;44:177-190. DOI: 10.1016/j.molcel.2011.07.019
13 - Tauriainen E, Luostarinen M, Martonen E, Finckenberg P, Kovalainen M, Huotari A, et al. Distinct effects of calorie restriction and resveratrol on diet-induced obesity and fatty liver formation. Journal of Nutrition and Metabolism. 2011;2011:525094. DOI: 10.1155/2011/525094
14 - Joseph AM, Adhihetty PJ, Buford TW, Wohlgemuth SE, Lees HA, Nguyen LM, et al. The impact of aging on mitochondrial function and biogenesis pathways in skeletal muscle of sedentary high- and low-functioning elderly individuals. Aging Cell. 2012;11:801-809. DOI: 10.1111/j.1474-9726.2012.00844.x
15 - Zeng L, Yang Y, Hu Y, Sun Y, Du Z, Xie Z, et al. Age-related decrease in the mitochondrial sirtuin deacetylase Sirt3 expression associated with ROS accumulation in the auditory cortex of the mimetic aging rat model. PLoS One. 2014;9:e88019. DOI: 10.1371/journal.pone.0088019
16 - Houtkooper RH, Pirinen E, Auwerx J. Sirtuins as regulators of metabolism and healthspan. Nature Reviews. Molecular Cell Biology. 2012;13:225-238. DOI: 10.1038/nrm3293
17 - Ozden O, Park SH, Kim HS, Jiang H, Coleman MC, Spitz DR, et al. Acetylation of MnSOD directs enzymatic activity responding to cellular nutrient status or oxidative stress. Aging (Albany NY). 2011;3:102-107. DOI: 10.1016/j.freeradbiomed.2014.08.001
18 - Porter GA, Urciuoli WR, Brookes PS, Nadtochiy SM. SIRT3 deficiency exacerbates ischemia-reperfusion injury: Implication for aged hearts. American Journal of Physiology. Heart and Circulatory Physiology. 2014;306:H1602-H1609. DOI: 10.1152/ajpheart.00027.2014
19 - Someya S, Yu W, Hallows WC, JZ X, Vann JM, Leeuwenburgh C, et al. Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction. Cell. 2010;143:802-812. DOI: 10.1016/j.cell.2010.10.002
20 - Tao RD, Coleman MC, Pennington JD, Ozden O, Park SH, Jiang HY, et al. Sirt3-mediated deacetylation of evolutionarily conserved lysine 122 regulates MnSOD activity in response to stress. Molecular Cell. 2010;40:893-904. DOI: 10.1016/j.molcel.2010.12.013
21 - D'Aquila P, Rose G, Panno ML, Passarino G, Bellizzi D. SIRT3 gene expression: A link between inherited mitochondrial DNA variants and oxidative stress. Gene. 2012;497:323-329. DOI: 10.1016/j.gene.2012.01.04
22 - Ozden O, Park SH, Wagner BA, Song HY, Zhu Y, Vassilopoulos A, et al. SIRT3 deacetylates and increases pyruvate dehydrogenase activity in cancer cells. Free Radical Biology & Medicine. 2014;76:163-172. DOI: 10.1016/j.freeradbiomed.2014.08.001
23 - Sack MN, Finkel T. Mitochondrial metabolism, sirtuins, and aging. Cold Spring Harbor Perspectives in Biology. 2012;4. DOI: 10.1101/cshperspect.a013102
24 - Chen CJ, YC F, Yu W, Wang W. SIRT3 protects cardiomyocytes from oxidative stress-mediated cell death by activating NF-kappaB. Biochemical and Biophysical Research Communications. 2013;430:798-803. DOI: 10.1016/j.bbrc.2012.11.066
25 - Jacobs KM, Pennington JD, Bisht KS, Aykin-Burns N, Kim HS, Mishra M, et al. SIRT3 interacts with the daf-16 homolog FOXO3a in the mitochondria, as well as increases FOXO3a dependent gene expression. International Journal of Biological Sciences. 2008;4:291-299
26 - Bellizzi D, Dato S, Cavalcante P, Covello G, Di Cianni F, Passarino G, et al. Characterization of a bidirectional promoter shared between two human genes related to aging: SIRT3 and PSMD13. Genomics. 2007;89:143-150. DOI: 10.1016/j.ygeno.2006.09.004
27 - Kong X, Wang R, Xue Y, Liu X, Zhang H, Chen Y, et al. Sirtuin 3, a new target of PGC-1alpha, plays an important role in the suppression of ROS and mitochondrial biogenesis. PLoS One. 2010;5:e11707. DOI: 10.1371/journal.pone.0011707
28 - Shi T, Wang F, Stieren E, Tong Q. SIRT3, a mitochondrial sirtuin deacetylase, regulates mitochondrial function and thermogenesis in brown adipocytes. The Journal of Biological Chemistry. 2005;280:13560-13567. DOI: 10.1074/jbc.M414670200
29 - Satterstrom FK, Swindell WR, Laurent G, Vyas S, Bulyk ML, Haigis MC. Nuclear respiratory factor 2 induces SIRT3 expression. Aging Cell. 2015;14:818-825. DOI: 10.1111/acel.12360
30 - Xiong Y, Wang M, Zhao J, Han Y, Jia L. Sirtuin 3: A Janus face in cancer (review). International Journal of Oncology. 2016;49:2227-2235. DOI: 10.3892/ijo.2016.3767
31 - Haigis MC, Guarente LP. Mammalian sirtuins—Emerging roles in physiology, aging, and calorie restriction. Genes & Development. 2006;20:2913-2921. DOI: 10.1101/gad.467506
32 - Weir HJ, Lane JD, Balthasar N. SIRT3: A central regulator of mitochondrial adaptation in health and disease. Genes & Cancer. 2013;4:118-124
33 - Haigis MC, Deng CX, Finley LW, Kim HS, Gius D. SIRT3 is a mitochondrial tumor suppressor: A scientific tale that connects aberrant cellular ROS, the Warburg effect, and carcinogenesis. Cancer Research. 2012;72:2468-2472. DOI: 10.1158/0008-5472.CAN-11-3633
34 - Park SH, Ozden O, Jiang H, Cha YI, Pennington JD, Aykin-Burns N, et al. Sirt3, mitochondrial ROS, ageing, and carcinogenesis. International Journal of Molecular Sciences. 2011;12:6226-6239. DOI: 10.3390/ijms12096226
35 - Zhu Y, Yan Y, Principe DR, Zou X, Vassilopoulos A, Gius D. SIRT3 and SIRT4 are mitochondrial tumor suppressor proteins that connect mitochondrial metabolism and carcinogenesis. Cancer Metab. 2014;2:15. DOI: 10.1186/2049-3002-2-15
36 - Lombard DB, Alt FW, Cheng HL, Bunkenborg J, Streeper RS, Mostoslavsky R, et al. Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation. Molecular and Cellular Biology. 2007;27:8807-8814. DOI: 10.1128/MCB.01636-07
37 - Hebert AS, Dittenhafer-Reed KE, Yu W, Bailey DJ, Selen ES, Boersma MD, et al. Calorie restriction and SIRT3 trigger global reprogramming of the mitochondrial protein acetylome. Molecular Cell. 2013;49:186-199. DOI: 10.1016/j.molcel.2012.10.024
38 - Kim HS, Patel K, Muldoon-Jacobs K, Bisht KS, Aykin-Burns N, Pennington JD, et al. SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell. 2010;17:41-52. DOI: 10.1016/j.ccr.2009.11.023
39 - Finley LW, Carracedo A, Lee J, Souza A, Egia A, Zhang J, et al. SIRT3 opposes reprogramming of cancer cell metabolism through HIF1alpha destabilization. Cancer Cell. 2011;19:416-428. DOI: 10.1016/j.ccr.2011.02.014
40 - Zhu Y, Park SH, Ozden O, Kim HS, Jiang H, Vassilopoulos A, et al. Exploring the electrostatic repulsion model in the role of Sirt3 in directing MnSOD acetylation status and enzymatic activity. Free Radical Biology & Medicine. 2012;53:828-833. DOI: 10.1016/j.freeradbiomed.2012.06.020
41 - Rangarajan P, Karthikeyan A, Lu J, Ling EA, Dheen ST. Sirtuin 3 regulates Foxo3a-mediated antioxidant pathway in microglia. Neuroscience. 2015;311:398-414. DOI: 10.1016/j.neuroscience.2015.10.048
42 - Sundaresan NR, Gupta M, Kim G, Rajamohan SB, Isbatan A, Gupta MP. Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice. The Journal of Clinical Investigation. 2009;119:2758-2771. DOI: 10.1172/JCI39162
43 - Heiden MGV, Cantley LC, Thompson CB. Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science. 2009;324:1029-1033. DOI: 10.1126/science.1160809
44 - DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB. The biology of cancer: Metabolic reprogramming fuels cell growth and proliferation. Cell Metabolism. 2008;7:11-20. DOI: 10.1016/j.cmet.2007.10.002
45 - Bell EL, Emerling BM, Ricoult SJH, Guarente L. SirT3 suppresses hypoxia inducible factor 1 alpha and tumor growth by inhibiting mitochondrial ROS production. Oncogene. 2011;30:2986-2996. DOI: 10.1038/onc.2011.37
46 - Yao WT, Ji SR, Qin Y, Yang JX, Xu J, Zhang B, et al. Profilin-1 suppresses tumorigenicity in pancreatic cancer through regulation of the SIRT3-HIF1 alpha axis. Molecular Cancer. 2014;13:1-12. DOI: 10.1186/1476-4598-13-187
47 - Ahn BH, Kim HS, Song S, Lee IH, Liu J, Vassilopoulos A, et al. A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis. Proceedings of the National Academy of Sciences of the United States of America. 2008;105:14447-14452. DOI: 10.1073/pnas.0803790105
48 - Fan J, Shan CL, Kang HB, Elf S, Xie JX, Tucker M, et al. Tyr phosphorylation of PDP1 toggles recruitment between ACAT1 and SIRT3 to regulate the pyruvate dehydrogenase complex. Molecular Cell. 2014;53:534-548. DOI: 10.1016/j.molcel.2013.12.026
49 - Shan CL, Kang HB, Elf S, Xie JX, TL G, Aguiar M, et al. Tyr-94 phosphorylation inhibits pyruvate dehydrogenase phosphatase 1 and promotes tumor growth. The Journal of Biological Chemistry. 2014;289:21413-21422. DOI: 10.1074/jbc.M114.581124
50 - Desouki MM, Doubinskaia I, Gius D, Abdulkadir SA. Decreased mitochondrial SIRT3 expression is a potential molecular biomarker associated with poor outcome in breast cancer. Human Pathology. 2014;45:1071-1077. DOI: 10.1016/j.humpath.2014.01.004
51 - Wei L, Zhou Y, Dai Q, Qiao C, Zhao L, Hui H, et al. Oroxylin A induces dissociation of hexokinase II from the mitochondria and inhibits glycolysis by SIRT3-mediated deacetylation of cyclophilin D in breast carcinoma. Cell Death & Disease. 2013;4:1-12. DOI: 10.1038/cddis.2013.131
52 - McGlynn LM, McCluney S, Jamieson NB, Thomson J, MacDonald AI, Oien K, et al. SIRT3 & SIRT7: Potential novel biomarkers for determining outcome in pancreatic cancer patients. PLoS One. 2015;10:e0131344. DOI: 10.1371/journal.pone.0131344
53 - Wang JX, Yi Y, Li YW, Cai XY, He HW, Ni XC, et al. Down-regulation of sirtuin 3 is associated with poor prognosis in hepatocellular carcinoma after resection. BMC Cancer. 2014;14:1-9. DOI: 10.1186/1471-2407-14-297
54 - Zhang B, Qin L, Zhou CJ, Liu YL, Qian HX, He SB. SIRT3 expression in hepatocellular carcinoma and its impact on proliferation and invasion of hepatoma cells. Asian Pacific Journal of Tropical Medicine. 2013;6:649-652. DOI: 10.1016/S1995-7645(13)60112-1
55 - Yu W, Denu RA, Krautkramer KA, Grindle KM, Yang DT, Asimakopoulos F, et al. Loss of SIRT3 provides growth advantage for B cell malignancies. The Journal of Biological Chemistry. 2016;291:3268-3279. DOI: 10.1074/jbc.M115.702076
56 - Dong XC, Jing LM, Wang WX, Gao YX. Down-regulation of SIRT3 promotes ovarian carcinoma metastasis. Biochemical and Biophysical Research Communications. 2016;475:245-250. DOI: 10.1016/j.bbrc.2016.05.098
57 - Marfe G, Tafani M, Indelicato M, Sinibaldi-Salimei P, Reali V, Pucci B, et al. Kaempferol induces apoptosis in two different cell lines via Akt inactivation, Bax and SIRT3 activation, and mitochondrial dysfunction. Journal of Cellular Biochemistry. 2009;106:643-650. DOI: 10.1002/jcb.22044
58 - Alhazzazi TY, Kamarajan P, Joo N, Huang JY, Verdin E, D'Silva NJ, et al. Sirtuin-3 (SIRT3), a novel potential therapeutic target for oral cancer. Cancer. 2011;117(8):1670. DOI: 10.1002/cncr.25676
59 - Torrens-Mas M, Pons DG, Sastre-Serra J, Oliver J, Roca P. SIRT3 silencing sensitizes breast cancer cells to cytotoxic treatments through an increment in ROS production. Journal of Cellular Biochemistry. 2016;118:397-406. DOI: 10.1002/jcb.25653
60 - Zhao Y, Yang H, Wang X, Zhang R, Wang C, Guo Z. Sirtuin-3 (SIRT3) expression is associated with overall survival in esophageal cancer. Annals of Diagnostic Pathology. 2013;17:483-485. DOI: 10.1016/j.anndiagpath.2013.06.001
61 - Cui Y, Qin L, Wu J, Qu X, Hou C, Sun W, et al. SIRT3 enhances glycolysis and proliferation in SIRT3-expressing gastric cancer cells. PLoS One. 2015;10:e0129834. DOI: 10.1371/journal.pone.0129834
62 - Liu C, Huang Z, Jiang H, Shi F. The sirtuin 3 expression profile is associated with pathological and clinical outcomes in colon cancer patients. BioMed Research International. 2014;2014:871263. DOI: 10.1155/2014/871263
63 - George J, Nihal M, Singh CK, Zhong W, Liu X, Ahmad N. Pro-proliferative function of mitochondrial sirtuin deacetylase SIRT3 in human melanoma. The Journal of Investigative Dermatology. 2016;136:809-818. DOI: 10.1016/j.jid.2015.12.026
64 - Iwahara T, Bonasio R, Narendra V, Reinberg D. SIRT3 functions in the nucleus in the control of stress-related gene expression. Molecular and Cellular Biology. 2012;32:5022-5034. DOI: 10.1128/MCB.00822-12
65 - Scher MB, Vaquero A, Reinberg D. SirT3 is a nuclear NAD+−dependent histone deacetylase that translocates to the mitochondria upon cellular stress. Genes & Development. 2007;21:920-928. DOI: 10.1101/gad.1527307
66 - Tao RD, Leclerc J, Yildiz K, Park SH, Jung B, Gius D, et al. Changes in gene expression in SIRT3 knockout liver cells. Turkish Journal of Biology. 2015;39:380-387. DOI: 10.1038/srep24156
67 - Ventura-Clapier R, Garnier A, Veksler V. Energy metabolism in heart failure. The Journal of Physiology. 2004;555:1-13. DOI: 10.1113/jphysiol.2003.055095
68 - Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. The New England Journal of Medicine. 2007;357:1121-1135. DOI: 10.1056/NEJMra071667
69 - Di Lisa F, Menabo R, Canton M, Barile M, Bernardi P. Opening of the mitochondrial permeability transition pore causes depletion of mitochondrial and cytosolic NAD+ and is a causative event in the death of myocytes in postischemic reperfusion of the heart. The Journal of Biological Chemistry. 2001;276:2571-2575. DOI: 10.1074/jbc.M006825200
70 - Hafner AV, Dai J, Gomes AP, Xiao CY, Palmeira CM, Rosenzweig A, et al. Regulation of the mPTP by SIRT3-mediated deacetylation of CypD at lysine 166 suppresses age-related cardiac hypertrophy. Aging (Albany NY). 2010;2:914-923. DOI: 10.18632/aging.100252
71 - DX H, Liu XB, Song WC, Wang JA. Roles of SIRT3 in heart failure: From bench to bedside. Journal of Zhejiang University. Science. B. 2016;17:821-830. DOI: 10.1631/jzus.B1600253
72 - Michishita E, Park JY, Burneskis JM, Barrett JC, Horikawa I. Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins. Molecular Biology of the Cell. 2005;16:4623-4635. DOI: 10.1091/mbc.E05-01-0033
73 - Winnik S, Auwerx J, Sinclair DA, Matter CM. Protective effects of sirtuins in cardiovascular diseases: From bench to bedside. European Heart Journal. 2015;36:3404-3412. DOI: 10.1093/eurheartj/ehv290
74 - Lanza IR, Short DK, Short KR, Raghavakaimal S, Basu R, Joyner MJ, et al. Endurance exercise as a countermeasure for aging. Diabetes. 2008;57:2933-2942. DOI: 10.2337/db08-0349
75 - Dittenhafer-Reed KE, Richards AL, Fan J, Smallegan MJ, Fotuhi Siahpirani A, Kemmerer ZA, et al. SIRT3 mediates multi-tissue coupling for metabolic fuel switching. Cell Metabolism. 2015;21:637-646. DOI: 10.1016/j.cmet.2015.03.007
76 - Parodi-Rullan R, Barreto-Torres G, Ruiz L, Casasnovas J, Javadov S. Direct renin inhibition exerts an anti-hypertrophic effect associated with improved mitochondrial function in post-infarction heart failure in diabetic rats. Cellular Physiology and Biochemistry. 2012;29:841-850. DOI: 10.1159/000178526
77 - Koentges C, Bode C, Bugger H. SIRT3 in cardiac physiology and disease. Frontiers in Cardiovascular Medicine. 2016;3:38. DOI: 10.3389/fcvm.2016.00038
78 - Bao W, Behm DJ, Nerurkar SS, Ao Z, Bentley R, Mirabile RC, et al. Effects of p38 MAPK inhibitor on angiotensin II-dependent hypertension, organ damage, and superoxide anion production. Journal of Cardiovascular Pharmacology. 2007;49:362-368. DOI: 10.1097/FJC.0b013e318046f34a
79 - Seddon M, Looi YH, Shah AM. Oxidative stress and redox signalling in cardiac hypertrophy and heart failure. Heart. 2007;93:903-907. DOI: 10.1136/hrt.2005.068270
80 - Ide T, Tsutsui H, Kinugawa S, Suematsu N, Hayashidani S, Ichikawa K, et al. Direct evidence for increased hydroxyl radicals originating from superoxide in the failing myocardium. Circulation Research. 2000;86:152-157
81 - Cave A, Grieve D, Johar S, Zhang M, Shah AM. NADPH oxidase-derived reactive oxygen species in cardiac pathophysiology. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 2005;360:2327-2334. DOI: 10.1098/rstb.2005.1772
82 - Nakamura K, Fushimi K, Kouchi H, Mihara K, Miyazaki M, Ohe T, et al. Inhibitory effects of antioxidants on neonatal rat cardiac myocyte hypertrophy induced by tumor necrosis factor-alpha and angiotensin II. Circulation. 1998;98:794-799
83 - Pimentel DR, Amin JK, Xiao L, Miller T, Viereck J, Oliver-Krasinski J, et al. Reactive oxygen species mediate amplitude-dependent hypertrophic and apoptotic responses to mechanical stretch in cardiac myocytes. Circulation Research. 2001;89:453-460
84 - Hirotani S, Otsu K, Nishida K, Higuchi Y, Morita T, Nakayama H, et al. Involvement of nuclear factor-kappaB and apoptosis signal-regulating kinase 1 in G-protein-coupled receptor agonist-induced cardiomyocyte hypertrophy. Circulation. 2002;105:509-515
85 - Li HL, Huang Y, Zhang CN, Liu G, Wei YS, Wang AB, et al. Epigallocathechin-3 gallate inhibits cardiac hypertrophy through blocking reactive oxidative species-dependent and -independent signal pathways. Free Radical Biology & Medicine. 2006;40:1756-1775
86 - Higuchi Y, Otsu K, Nishida K, Hirotani S, Nakayama H, Yamaguchi O, et al. Involvement of reactive oxygen species-mediated NF-kappa B activation in TNF-alpha-induced cardiomyocyte hypertrophy. Journal of Molecular and Cellular Cardiology. 2002;34:233-240. DOI: 10.1006/jmcc.2001.1505
87 - Adiga IK, Nair RR. Multiple signaling pathways coordinately mediate reactive oxygen species dependent cardiomyocyte hypertrophy. Cell Biochemistry and Function. 2008;26:346-351. DOI: 10.1002/cbf.1449
88 - Koentges C, Pfeil K, Schnick T, Wiese S, Dahlbock R, Cimolai MC, et al. SIRT3 deficiency impairs mitochondrial and contractile function in the heart. Basic Research in Cardiology. 2015;110:36. DOI: 10.1007/s00395-015-0493-6
89 - Paulin R, Dromparis P, Sutendra G, Gurtu V, Zervopoulos S, Bowers L, et al. Sirtuin 3 deficiency is associated with inhibited mitochondrial function and pulmonary arterial hypertension in rodents and humans. Cell Metabolism. 2014;20:827-839. DOI: 10.1016/j.cmet.2014.08.011
90 - Parodi-Rullan RM, Chapa-Dubocq X, Rullan PJ, Jang S, Javadov S. High sensitivity of SIRT3 deficient hearts to ischemia-reperfusion is associated with mitochondrial abnormalities. Frontiers in Pharmacology. 2017;8. DOI: 10.3389/fphar.2017.00275
91 - Sundaresan NR, Samant SA, Pillai VB, Rajamohan SB, Gupta MP. SIRT3 is a stress-responsive deacetylase in cardiomyocytes that protects cells from stress-mediated cell death by deacetylation of Ku70. Molecular and Cellular Biology. 2008;28:6384-6401. DOI: 10.1128/MCB.00426-08
92 - Hirschey MD, Shimazu T, Goetzman E, Jing E, Schwer B, Lombard DB, et al. SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature. 2010;464:121-125. DOI: 10.1038/nature08778
93 - Zeng H, Vaka VR, He X, Booz GW, Chen JX. High-fat diet induces cardiac remodelling and dysfunction: Assessment of the role played by SIRT3 loss. Journal of Cellular and Molecular Medicine. 2015;19:1847-1856. DOI: 10.1111/jcmm.12556
94 - Du Q, Zhu B, Zhai Q, Yu B. Sirt3 attenuates doxorubicin-induced cardiac hypertrophy and mitochondrial dysfunction via suppression of Bnip3. American Journal of Translational Research. 2017;9:3360-3373
95 - Cheung KG, Cole LK, Xiang B, Chen K, Ma X, Myal Y, et al. Sirtuin-3 (SIRT3) protein attenuates doxorubicin-induced oxidative stress and improves mitochondrial respiration in H9c2 cardiomyocytes. The Journal of Biological Chemistry. 2015;290:10981-10993. DOI: 10.1074/jbc.M114.607960
96 - Zhou X, Chen M, Zeng X, Yang J, Deng H, Yi L, et al. Resveratrol regulates mitochondrial reactive oxygen species homeostasis through Sirt3 signaling pathway in human vascular endothelial cells. Cell Death & Disease. 2014;5:e1576. DOI: 10.1038/cddis.2014.530
97 - Quan Y, Xia L, Shao J, Yin S, Cheng CY, Xia W, et al. Adjudin protects rodent cochlear hair cells against gentamicin ototoxicity via the SIRT3-ROS pathway. Scientific Reports. 2015;5:8181. DOI: 10.1038/srep08181
98 - Yu L, Gong B, Duan W, Fan C, Zhang J, Li Z, et al. Melatonin ameliorates myocardial ischemia/reperfusion injury in type 1 diabetic rats by preserving mitochondrial function: Role of AMPK-PGC-1alpha-SIRT3 signaling. Scientific Reports. 2017;7:41337. DOI: 10.1038/srep41337
99 - Pillai VB, Kanwal A, Fang YH, Sharp WW, Samant S, Arbiser J, et al. Honokiol, an activator of Sirtuin-3 (SIRT3) preserves mitochondria and protects the heart from doxorubicin-induced cardiomyopathy in mice. Oncotarget. 2017;8:34082-34098. DOI: 10.18632/oncotarget.16133
100 - Pillai VB, Bindu S, Sharp W, Fang YH, Kim G, Gupta M, et al. Sirt3 protects mitochondrial DNA damage and blocks the development of doxorubicin-induced cardiomyopathy in mice. American Journal of Physiology. Heart and Circulatory Physiology. 2016;310:H962-H972. DOI: 10.1152/ajpheart.00832.2015
101 - You J, Yue Z, Chen S, Chen Y, Lu X, Zhang X, et al. Receptor-interacting protein 140 represses sirtuin 3 to facilitate hypertrophy, mitochondrial dysfunction and energy metabolic dysfunction in cardiomyocytes. Acta Physiologica (Oxford, England). 2017;220:58-71. DOI: 10.1111/apha.12800
102 - Zheng Z, Ma H, Zhang X, Tu F, Wang X, Ha T, et al. Enhanced glycolytic metabolism contributes to cardiac dysfunction in polymicrobial sepsis. The Journal of Infectious Diseases. 2017;215:1396-1406. DOI: 10.1093/infdis/jix138
103 - Sun D, Yang F. Metformin improves cardiac function in mice with heart failure after myocardial infarction by regulating mitochondrial energy metabolism. Biochemical and Biophysical Research Communications. 2017;486:329-335. DOI: 10.1016/j.bbrc.2017.03.036