SIRT3 Is a Mitochondria-Localized Tumor Suppressor Required for Maintenance of Mitochondrial Integrity and Metabolism during Stress

Kim, Hyun‐Seok; Patel, Krish; Muldoon-Jacobs, Kristi; Bisht, Kheem S.; Aykin-Burns, Nūkhet; Pennington, J. Daniel; Meer, Riet van der; Nguyen, Phuongmai; Savage, Jason E.; Owens, Kjerstin M.; Vassilopoulos, Athanassios; Özden, Özkan; Park, Seong Hoon; Singh, Keshav K.; Abdulkadir, Sarki A.; Spitz, Douglas R.; Deng, Chu Xia; Gius, David

doi:10.1016/j.ccr.2009.11.023

Cited by 716 publications

(840 citation statements)

References 34 publications

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“…Furthermore, SIRT3 is the major deacetylase in the mitochondrion (99). SIRT3 deacetylates FOXO3a, which strengthens the DNA-binding of FOXO3a, but does not change the mitochondrial location of FOXO3a (100). It has been demonstrated that FOXO3a forms a complex with SIRT3 and mitochondrial RNA polymerase, binding to mitochondrial DNA, and further increasing the expression of oxidative phosphorylation-associated proteins, ultimately, increasing mitochondrial respiration (59).…”

Section: Acetylation Of Foxo Proteinsmentioning

confidence: 99%

Post-translational modifications of FOXO family proteins

Wang

Huang

2016

Molecular Medicine Reports

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Abstract. The Forkhead box O (FOXO) protein family is predominantly involved in apoptosis, oxidative stress, DNA damage/repair, tumor angiogenesis, glycometabolism, regulating life span and other important biological processes. Its activity is affected by a variety of posttranslational modifications (PTMs), including phosphorylation, acetylation, ubiquitination, methylation and glycosylation. When cells are subjected to different environments, the corresponding PTMs act on the FOXO protein family, to change transcriptional activity or subcellular localization, and the expression of downstream target genes, will ultimately affect the biological behavior of the cells. In this review, we will discuss the biological characteristics of FOXO protein PTMs.

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Section: Acetylation Of Foxo Proteinsmentioning

confidence: 99%

Post-translational modifications of FOXO family proteins

Wang

Huang

2016

Molecular Medicine Reports

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“…It regulates mitochondrial activity by ROS in many cell types and modulates CREB phosphorylation and fat metabolism (Shi et al ., 2005; Hirschey et al ., 2010; Kim et al ., 2010). Importantly, SIRT3 has an essential role in enhancing the mitochondrial antioxidant glutathione, which could contribute to reduce aging in mammals (Someya et al ., 2010).…”

Section: Introductionmentioning

confidence: 99%

SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer's disease

et al. 2017

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SummaryAlzheimer's disease (AD) is the leading cause of dementia in the elderly. Despite decades of study, effective treatments for AD are lacking. Mitochondrial dysfunction has been closely linked to the pathogenesis of AD, but the relationship between mitochondrial pathology and neuronal damage is poorly understood. Sirtuins (SIRT, silent mating type information regulation 2 homolog in yeast) are NAD‐dependent histone deacetylases involved in aging and longevity. The objective of this study was to investigate the relationship between SIRT3 and mitochondrial function and neuronal activity in AD. SIRT3 mRNA and protein levels were significantly decreased in AD cerebral cortex, and Ac‐p53 K320 was significantly increased in AD mitochondria. SIRT3 prevented p53‐induced mitochondrial dysfunction and neuronal damage in a deacetylase activity‐dependent manner. Notably, mitochondrially targeted p53 (mito‐p53) directly reduced mitochondria DNA‐encoded ND2 and ND4 gene expression resulting in increased reactive oxygen species (ROS) and reduced mitochondrial oxygen consumption. ND2 and ND4 gene expressions were significantly decreased in patients with AD. p53‐ChIP analysis verified the presence of p53‐binding elements in the human mitochondrial genome and increased p53 occupancy of mitochondrial DNA in AD. SIRT3 overexpression restored the expression of ND2 and ND4 and improved mitochondrial oxygen consumption by repressing mito‐p53 activity. Our results indicate that SIRT3 dysfunction leads to p53‐mediated mitochondrial and neuronal damage in AD. Therapeutic modulation of SIRT3 activity may ameliorate mitochondrial pathology and neurodegeneration in AD.

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“…SIRT3 is a soluble mitochondrial protein highly expressed in mitochondrial rich tissues and also plays critical roles related to tumor suppression, cellular stress, fat acid metabolism, oxidative stress response, and age-associated hearing loss (Hirschey et al, 2010;Kim et al, 2010;Someya et al, 2010). Lombard et al (2007) found that no abnormalities were identified in SIRT3-deficient mice under non-stress conditions; however, the hyperacetylation of mitochondrial proteins was observed when stress was applied.…”

Section: Characteristics and Functions Of Sirt3mentioning

confidence: 99%

“…Fortunately, SIRT3 has been demonstrated to participate in numerous biological processes including anti-oxidation reactions, cell survival, and mitochondrial protection, all of which could contribute to the treatment of ischemic heart disease (Kim et al, 2010;Someya et al, 2010;Dittenhafer-Reed et al, 2015). Since loss of cardiomyocytes due to cell death is the main cause of cardiac dysfunction following MI, inhibition of apoptosis or necrosis is a critical necessity.…”

Section: Role Of Sirt3 In Attenuating Ischemia And/or Reperfusion-indmentioning

confidence: 99%

Roles of SIRT3 in heart failure: from bench to bedside

Liu

Song

et al. 2016

J. Zhejiang Univ. Sci. B

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Heart failure (HF) represents the most common endpoint of most cardiovascular diseases (CVDs) which are the leading causes of death around the world. Despite the advances in treating CVDs, the prevalence of HF continues to increase. It is believed that better results of prognosis are obtained from prevention rather than additional treatment for HF. Therefore, it is reasonable to prevent the development of CVDs or other complications to HF. Most types of HF are attributed to contractile dysfunction, cardiac hypertrophy or remodeling, and ischemic injuries. SIRT3 is a mitochondrial nicotinamide adenine dinucleotide (NAD + )-dependent deacetylase whose substrates vary from metabolic biogenesis-associated proteins to stress-responsive proteins. In recent years, a number of studies have highlighted the cardio-protective role of SIRT3 and, as such, efforts have been made to induce over-expression or increased activity of this protein. In this review, we provide an overview of the roles of SIRT3 in cardiac hypertrophy induced by pressure overload or agonists and cardiomyocytes ischemic injuries. Moreover, we will introduce the application of SIRT3 agonists in the prevention of cardiac hypertrophy and ischemia reperfusion injury.

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SIRT3 Is a Mitochondria-Localized Tumor Suppressor Required for Maintenance of Mitochondrial Integrity and Metabolism during Stress

Cited by 716 publications

References 34 publications

Post-translational modifications of FOXO family proteins

Post-translational modifications of FOXO family proteins

SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer's disease

Roles of SIRT3 in heart failure: from bench to bedside

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