SIRT3 Protein Deacetylates Isocitrate Dehydrogenase 2 (IDH2) and Regulates Mitochondrial Redox Status

Yu, Wei; Dittenhafer‐Reed, Kristin E.; Denu, John M.

doi:10.1074/jbc.m112.355206

Cited by 377 publications

(320 citation statements)

References 53 publications

(55 reference statements)

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“…Keratinocytes-SIRT3 acts through several targets to both reduce superoxide production and enhance the oxidative stress response and detoxification mechanisms (8,(11)(12)(13)(14)(15)(16)(17). Consistent with the repression of mitochondrial oxidative stress by SIRT3, mitochondrial superoxide levels decreased in SIRT3-overexpressing keratinocytes (Fig.…”

Section: Sirt3 Modulates Mitochondrial Superoxide Levels Insupporting

confidence: 62%

“…Decreased availability of the sirtuin co-substrate NAD ϩ may lead to decreased SIRT3 activity in keratinocytes during differentiation. Given the well established role of SIRT3 as a regulator of mitochondrial oxidative stress (8,(11)(12)(13)(14)(15)(16)(17)(18), mitochondrial superoxide levels increased in both primary and immortalized keratinocytes with differentiation. We identified SIRT3 as a key regulator of this phenotype; constitutive SIRT3 deficiency resulted in increased mitochondrial superoxide levels, whereas constitutive SIRT3 expression reduced mitochondrial ROS.…”

Section: Discussionmentioning

confidence: 99%

“…The mitochondrial sirtuin SIRT3 is uniquely poised to modulate both the generation of ROS and the detoxification of harmful free radicals, protecting cells from mitochondrial oxidative stress (8,11,17,18). Loss of SIRT3 triggers ROS and oxidative damage, affecting distinct cellular processes and promoting phenotypes of aging (13,14).…”

Section: Discussionmentioning

confidence: 99%

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The Protein Deacetylase SIRT3 Prevents Oxidative Stress-induced Keratinocyte Differentiation

Bause

Matsui

Haigis

2013

Journal of Biological Chemistry

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Background: SIRT3 plays a major role in protecting against mitochondrial oxidative stress. Results: Oxidative stress increases during keratinocyte differentiation, and SIRT3 can decrease differentiation by attenuating oxidative stress. Conclusion: SIRT3-induced down-regulation of mitochondrial oxidative stress attenuates keratinocyte differentiation. Significance: Understanding the regulation of keratinocyte differentiation is crucial for developing new therapies against dysregulated skin differentiation and aging.

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Section: Sirt3 Modulates Mitochondrial Superoxide Levels Insupporting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

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The Protein Deacetylase SIRT3 Prevents Oxidative Stress-induced Keratinocyte Differentiation

Bause

Matsui

Haigis

2013

Journal of Biological Chemistry

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“…However, despite a likely role for increased ROS production, it is not possible from the present study to determine whether impaired insulin secretion following SIRT3 knockdown occurred as a result of a primary defect in insulin secretion or as a consequence of increased beta cell apoptosis. The precise mechanisms governing increased ROS production in INS1 cells are unclear; however, in different tissues, SIRT3 has been reported to alter the acetylation status of a number of proteins linked to ROS production [20,23,[40][41][42][43].…”

Section: Discussionmentioning

confidence: 99%

Sirtuin 3 regulates mouse pancreatic beta cell function and is suppressed in pancreatic islets isolated from human type 2 diabetic patients

et al. 2013

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Aims/hypothesis Sirtuin (SIRT)3 is a mitochondrial protein deacetylase that regulates reactive oxygen species (ROS) production and exerts anti-inflammatory effects. As chronic inflammation and mitochondrial dysfunction are key factors mediating pancreatic beta cell impairment in type 2 diabetes, we investigated the role of SIRT3 in the maintenance of beta cell function and mass in type 2 diabetes. Methods We analysed changes in SIRT3 expression in experimental models of type 2 diabetes and in human islets isolated from type 2 diabetic patients. We also determined the effects of SIRT3 knockdown on beta cell function and mass in INS1 cells. Results SIRT3 expression was markedly decreased in islets isolated from type 2 diabetes patients, as well as in mouse islets or INS1 cells incubated with IL1β and TNFα. SIRT3 knockdown in INS1 cells resulted in lowered insulin secretion, increased beta cell apoptosis and reduced expression of key beta cell genes. SIRT3 knockdown also blocked the protective effects of nicotinamide mononucleotide on proinflammatory cytokines in beta cells. The deleterious effects of SIRT3 knockdown were mediated by increased levels of cellular ROS and IL1β. Conclusions/interpretation Decreased beta cell SIRT3 levels could be a key step in the onset of beta cell dysfunction, occurring via abnormal elevation of ROS levels and amplification of beta cell IL1β synthesis. Strategies to increase the activity or levels of SIRT3 could generate attractive therapies for type 2 diabetes.

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“…Functional studies showed that SIRT3 regulates mitochondrial biogenesis, and it is correlated with the expression of genes related to mitochondrial function, including PGC1α and UCP1 (Kong et al, 2010;Shi et al, 2005). Moreover, SIRT3 deacetylates isocitrate dehydrogenase 2 (IDH2) and regulates mitochondrial redox status (Yu et al, 2012). A recent study suggested that SIRT3 was regulated by nutrient excess.…”

Section: Sirt3mentioning

confidence: 99%

Do Sirtuins Promote Mammalian Longevity?: A Critical Review on Its Relevance to the Longevity Effect Induced by Calorie Restriction

Park

Mori

Shimokawa

2013

Molecules and Cells

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Sirtuins (SIRTs), a family of nicotinamide adenine dinucleotide (NAD)-dependent deacetylases, are emerging as key molecules that regulate aging and age-related diseases including cancers, metabolic disorders, and neurodegenerative diseases. Seven isoforms of SIRT (SIRT1-7) have been identified in mammals. SIRT1 and 6, mainly localized in the nucleus, regulate transcription of genes and DNA repair. SIRT3 in the mitochondria regulates mitochondrial bioenergetics. Initial studies in yeasts, nematodes, and flies indicated a strong connection of SIRT with the life-prolonging effects of calorie restriction (CR), a robust experimental intervention for longevity in a range of organisms. However, subsequent studies reported controversial findings regarding SIRT roles in the effect of CR. This review describes the functional roles of mammalian SIRTs and discusses their relevance to mechanisms underlying the longevity effect of CR.

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SIRT3 Protein Deacetylates Isocitrate Dehydrogenase 2 (IDH2) and Regulates Mitochondrial Redox Status

Abstract: Background: NAD ϩ -dependent deacetylase SIRT3 is essential for the prevention of age-related hearing loss during caloric

Cited by 377 publications

References 53 publications

The Protein Deacetylase SIRT3 Prevents Oxidative Stress-induced Keratinocyte Differentiation

The Protein Deacetylase SIRT3 Prevents Oxidative Stress-induced Keratinocyte Differentiation

Sirtuin 3 regulates mouse pancreatic beta cell function and is suppressed in pancreatic islets isolated from human type 2 diabetic patients

Do Sirtuins Promote Mammalian Longevity?: A Critical Review on Its Relevance to the Longevity Effect Induced by Calorie Restriction

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