SIRT3 deacetylates FOXO3 to protect mitochondria against oxidative damage.
TL;DR: The finding that SIRT3 deacetylates FOXO3 to protect mitochondria against oxidative stress provides a possible direction for aging-delaying therapies and disease intervention.
About: This article is published in Free Radical Biology and Medicine.The article was published on 2013-10-01. It has received 329 citations till now. The article focuses on the topics: Mitochondrial biogenesis & Mitophagy.
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TL;DR: The role of HDACs in cancer and the therapeutic potential ofHDAC inhibitors (HDACi) as emerging drugs in cancer treatment are discussed.
Abstract: Over the last several decades, it has become clear that epigenetic abnormalities may be one of the hallmarks of cancer. Posttranslational modifications of histones, for example, may play a crucial role in cancer development and progression by modulating gene transcription, chromatin remodeling, and nuclear architecture. Histone acetylation, a well-studied posttranslational histone modification, is controlled by the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). By removing acetyl groups, HDACs reverse chromatin acetylation and alter transcription of oncogenes and tumor suppressor genes. In addition, HDACs deacetylate numerous nonhistone cellular substrates that govern a wide array of biological processes including cancer initiation and progression. This review will discuss the role of HDACs in cancer and the therapeutic potential of HDAC inhibitors (HDACi) as emerging drugs in cancer treatment.
724 citations
Cites background from "SIRT3 deacetylates FOXO3 to protect..."
...SIRT3, a mitochondrial deacetylase, evokes mitophagy under oxidative stress or starvation conditions (Tseng et al. 2013; Webster et al. 2013)....
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TL;DR: Of particular interest are the dual role played by FoxOs in cancer development and their key role in whole body nutrient homeostasis, modulating metabolic adaptations and/or disturbances in response to low vs. high nutrient intake.
Abstract: Transcription factors of the forkhead box, class O (FoxO) family are important regulators of the cellular stress response and promote the cellular antioxidant defense. On one hand, FoxOs stimulate the transcription of genes coding for antioxidant proteins located in different subcellular compartments, such as in mitochondria (i.e. superoxide dismutase-2, peroxiredoxins 3 and 5) and peroxisomes (catalase), as well as for antioxidant proteins found extracellularly in plasma (e.g., selenoprotein P and ceruloplasmin). On the other hand, reactive oxygen species (ROS) as well as other stressful stimuli that elicit the formation of ROS, may modulate FoxO activity at multiple levels, including posttranslational modifications of FoxOs (such as phosphorylation and acetylation), interaction with coregulators, alterations in FoxO subcellular localization, protein synthesis and stability. Moreover, transcriptional and posttranscriptional control of the expression of genes coding for FoxOs is sensitive to ROS. Here, we review these aspects of FoxO biology focusing on redox regulation of FoxO signaling, and with emphasis on the interplay between ROS and FoxOs under various physiological and pathophysiological conditions. Of particular interest are the dual role played by FoxOs in cancer development and their key role in whole body nutrient homeostasis, modulating metabolic adaptations and/or disturbances in response to low vs. high nutrient intake. Examples discussed here include calorie restriction and starvation as well as adipogenesis, obesity and type 2 diabetes.
533 citations
TL;DR: Results in animal and cellular models of AD and in patients with sporadic late-onset AD suggest that impaired mitophagy contributes to synaptic dysfunction and cognitive deficits by triggering Aβ and Tau accumulation through increases in oxidative damage and cellular energy deficits; these, in turn, impairMitophagy.
479 citations
Cites background from "SIRT3 deacetylates FOXO3 to protect..."
...SIRT3 activates FOXO3 to induce p62 (a major autophagy protein) clustering on ubiquitinated mitochondrial substrates and formation of autolysosomes [85]....
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TL;DR: There is translational evidence for a role of sirtuins in patients with endothelial dysfunction, type 1 or type 2 diabetes and longevity, and it is anticipated that this field will move quickly from bench to bedside.
Abstract: Sirtuins (Sirt1–Sirt7) comprise a family of nicotinamide adenine dinucleotide (NAD+)-dependent enzymes. While deacetylation reflects their main task, some of them have deacylase, adenosine diphosphate-ribosylase, demalonylase, glutarylase, and desuccinylase properties. Activated upon caloric restriction and exercise, they control critical cellular processes in the nucleus, cytoplasm, and mitochondria to maintain metabolic homeostasis, reduce cellular damage and dampen inflammation—all of which serve to protect against a variety of age-related diseases, including cardiovascular pathologies. This review focuses on the cardiovascular effects of Sirt1, Sirt3, Sirt6, and Sirt7. Most is known about Sirt1. This deacetylase protects from endothelial dysfunction, atherothrombosis, diet-induced obesity, type 2 diabetes, liver steatosis, and myocardial infarction. Sirt3 provides beneficial effects in the context of left ventricular hypertrophy, cardiomyopathy, oxidative stress, metabolic homeostasis, and dyslipidaemia. Sirt6 is implicated in ameliorating dyslipidaemia, cellular senescence, and left ventricular hypertrophy. Sirt7 plays a role in lipid metabolism and cardiomyopathies. Most of these data were derived from experimental findings in genetically modified mice, where NFκB, Pcsk9, low-density lipoprotein-receptor, PPARγ, superoxide dismutase 2, poly[adenosine diphosphate-ribose] polymerase 1, and endothelial nitric oxide synthase were identified among others as crucial molecular targets and/or partners of sirtuins. Of note, there is translational evidence for a role of sirtuins in patients with endothelial dysfunction, type 1 or type 2 diabetes and longevity. Given the availability of specific Sirt1 activators or pan-sirtuin activators that boost levels of the sirtuin cofactor NAD+, we anticipate that this field will move quickly from bench to bedside.
336 citations
Cites background from "SIRT3 deacetylates FOXO3 to protect..."
...malian cardiomyocytes and to protect endothelial mitochondria from oxidative damage.(31,41)...
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TL;DR: This statement will define the key roles that mitochondria play in cardiovascular physiology and disease and provide insight into how mitochondrial defects can contribute to cardiovascular disease; it will also discuss potential biomarkers of mitochondrial disease and suggest potential novel therapeutic approaches.
Abstract: Cardiovascular disease is a major leading cause of morbidity and mortality in the United States and elsewhere. Alterations in mitochondrial function are increasingly being recognized as a contributing factor in myocardial infarction and in patients presenting with cardiomyopathy. Recent understanding of the complex interaction of the mitochondria in regulating metabolism and cell death can provide novel insight and therapeutic targets. The purpose of this statement is to better define the potential role of mitochondria in the genesis of cardiovascular disease such as ischemia and heart failure. To accomplish this, we will define the key mitochondrial processes that play a role in cardiovascular disease that are potential targets for novel therapeutic interventions. This is an exciting time in mitochondrial research. The past decade has provided novel insight into the role of mitochondria function and their importance in complex diseases. This statement will define the key roles that mitochondria play in cardiovascular physiology and disease and provide insight into how mitochondrial defects can contribute to cardiovascular disease; it will also discuss potential biomarkers of mitochondrial disease and suggest potential novel therapeutic approaches.
291 citations
References
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TL;DR: It is demonstrated that SIRT3 modulates mitochondrial intermediary metabolism and fatty-acid use during fasting and acetylation is identified as a novel regulatory mechanism for mitochondrial fatty- acid oxidation.
Abstract: Sirtuins are NAD(+)-dependent protein deacetylases. They mediate adaptive responses to a variety of stresses, including calorie restriction and metabolic stress. Sirtuin 3 (SIRT3) is localized in the mitochondrial matrix, where it regulates the acetylation levels of metabolic enzymes, including acetyl coenzyme A synthetase 2 (refs 1, 2). Mice lacking both Sirt3 alleles appear phenotypically normal under basal conditions, but show marked hyperacetylation of several mitochondrial proteins. Here we report that SIRT3 expression is upregulated during fasting in liver and brown adipose tissues. During fasting, livers from mice lacking SIRT3 had higher levels of fatty-acid oxidation intermediate products and triglycerides, associated with decreased levels of fatty-acid oxidation, compared to livers from wild-type mice. Mass spectrometry of mitochondrial proteins shows that long-chain acyl coenzyme A dehydrogenase (LCAD) is hyperacetylated at lysine 42 in the absence of SIRT3. LCAD is deacetylated in wild-type mice under fasted conditions and by SIRT3 in vitro and in vivo; and hyperacetylation of LCAD reduces its enzymatic activity. Mice lacking SIRT3 exhibit hallmarks of fatty-acid oxidation disorders during fasting, including reduced ATP levels and intolerance to cold exposure. These findings identify acetylation as a novel regulatory mechanism for mitochondrial fatty-acid oxidation and demonstrate that SIRT3 modulates mitochondrial intermediary metabolism and fatty-acid use during fasting.
1,339 citations
TL;DR: The recent progress in sirtuin biology, the role these proteins have in various age-related diseases and the tantalizing notion that the activity of this family of enzymes somehow regulates how long the authors live are reviewed.
Abstract: The sirtuins are a highly conserved family of NAD(+)-dependent enzymes that regulate lifespan in lower organisms. Recently, the mammalian sirtuins have been connected to an ever widening circle of activities that encompass cellular stress resistance, genomic stability, tumorigenesis and energy metabolism. Here we review the recent progress in sirtuin biology, the role these proteins have in various age-related diseases and the tantalizing notion that the activity of this family of enzymes somehow regulates how long we live.
1,339 citations
"SIRT3 deacetylates FOXO3 to protect..." refers background in this paper
...SIRT3 is localized in mitochondria and serves as a primary regulator of mitochondrial protein acetylation [5,6]....
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TL;DR: How mitochondrial dynamics is altered in these neurodegenerative diseases is reviewed and the reciprocal interactions between mitochondrial fusion, fission, transport and mitophagy are discussed.
Abstract: Neurons are metabolically active cells with high energy demands at locations distant from the cell body. As a result, these cells are particularly dependent on mitochondrial function, as reflected by the observation that diseases of mitochondrial dysfunction often have a neurodegenerative component. Recent discoveries have highlighted that neurons are reliant particularly on the dynamic properties of mitochondria. Mitochondria are dynamic organelles by several criteria. They engage in repeated cycles of fusion and fission, which serve to intermix the lipids and contents of a population of mitochondria. In addition, mitochondria are actively recruited to subcellular sites, such as the axonal and dendritic processes of neurons. Finally, the quality of a mitochondrial population is maintained through mitophagy, a form of autophagy in which defective mitochondria are selectively degraded. We review the general features of mitochondrial dynamics, incorporating recent findings on mitochondrial fusion, fission, transport and mitophagy. Defects in these key features are associated with neurodegenerative disease. Charcot-Marie-Tooth type 2A, a peripheral neuropathy, and dominant optic atrophy, an inherited optic neuropathy, result from a primary deficiency of mitochondrial fusion. Moreover, several major neurodegenerative diseases—including Parkinson's, Alzheimer's and Huntington's disease—involve disruption of mitochondrial dynamics. Remarkably, in several disease models, the manipulation of mitochondrial fusion or fission can partially rescue disease phenotypes. We review how mitochondrial dynamics is altered in these neurodegenerative diseases and discuss the reciprocal interactions between mitochondrial fusion, fission, transport and mitophagy.
1,323 citations
"SIRT3 deacetylates FOXO3 to protect..." refers background in this paper
...Mitochondrial quality is also secured through the mitochondrial fission and fusion [2,27,28]....
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...The induction of Mfn2 by SIRT3–FOXO3 could promote mitochondrial fusion to mediate repair of damaged mitochondrial DNA [27,28], whereas the enhancement of Drp1...
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...BAECs were cotransfected with siRNA and DNA constructs using Lipofectamine 2000 (Invitrogen)....
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...and Fis1 could trigger the isolation of damaged mitochondria from healthy mitochondria so that they can be targeted for degradation [27,28]....
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...Consequently, the oxidative damage to nuclear DNA is suppressed and the nuclear redox signaling is affected, the effects of which enhance cellular tolerance to oxidative damage [45]....
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TL;DR: It is shown that Sirt3 functions in vivo to regulate and maintain basal ATP levels and as a regulator of mitochondrial electron transport and implicate protein acetylation as an important regulator of Complex I activity.
Abstract: Here, we demonstrate a role for the mitochondrial NAD-dependent deacetylase Sirt3 in the maintenance of basal ATP levels and as a regulator of mitochondrial electron transport. We note that Sirt3−/− mouse embryonic fibroblasts have a reduction in basal ATP levels. Reconstitution with wild-type but not a deacetylase-deficient form of Sirt3 restored ATP levels in these cells. Furthermore in wild-type mice, the resting level of ATP correlates with organ-specific Sirt3 protein expression. Remarkably, in mice lacking Sirt3, basal levels of ATP in the heart, kidney, and liver were reduced >50%. We further demonstrate that mitochondrial protein acetylation is markedly elevated in Sirt3−/− tissues. In addition, in the absence of Sirt3, multiple components of Complex I of the electron transport chain demonstrate increased acetylation. Sirt3 can also physically interact with at least one of the known subunits of Complex I, the 39-kDa protein NDUFA9. Functional studies demonstrate that mitochondria from Sirt3−/− animals display a selective inhibition of Complex I activity. Furthermore, incubation of exogenous Sirt3 with mitochondria can augment Complex I activity. These results implicate protein acetylation as an important regulator of Complex I activity and demonstrate that Sirt3 functions in vivo to regulate and maintain basal ATP levels.
1,145 citations
"SIRT3 deacetylates FOXO3 to protect..." refers background in this paper
...Increased expression of SIRT3 in adipocytes induces the expression of genes involved in mitochondrial biogenesis [23] and the maintenance of cellular ATP levels in heart, liver, and kidney [24]....
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TL;DR: It is shown that the protective effects of CR on oxidative stress and damage are diminished in mice lacking SIRT3, a mitochondrial deacetylase, a major mitochondrial antioxidant enzyme.
1,123 citations
"SIRT3 deacetylates FOXO3 to protect..." refers background in this paper
...All these results indicate that SIRT3-mediated deacetylation of FOXO3 at K271 and K290 induces the mitophagic system to eliminate ROSdamaged mitochondria and protect cells against oxidative stress....
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...Highfat diet feeding in mice leads to a significantly elevated ROS accumulation, reduced mitochondrial density, downregulation of PGC-1α and TFAM, increased mitochondrial dysfunction, and increment in FOXO3 phosphorylation [49]....
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...However, increased mitochondrial biogenesis is accompanied by the generation of ROS, which interferes with the insulin signaling pathway and leads to the progression of insulin resistance [48]....
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...SIRT3-mediated deacetylation of FOXO3 reduces levels of cellular ROS by upregulating the antioxidant enzymes manganese superoxide dismutase and catalase, which further ameliorates cardiac hypertrophy in mice [7,16]....
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...Hence, SIRT3–FOXO3 may improve insulin resistance by enhancing mitochondrial biogenesis and the mitochondrial ROS-detoxifying system, thereby mitigating the onset and progression of diabetes and obesity....
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