SIRT3 Deficiency and Mitochondrial Protein Hyperacetylation Accelerate the Development of the Metabolic Syndrome

Hirschey, Matthew D.; Shimazu, Tadahiro; Jing, Enxuan; Grueter, Carrie A.; Collins, Amy; Aouizerat, Bradley E.; Stančáková, Alena; Goetzman, Eric S.; Lam, Maggie M.; Schwer, Bjoern; Stevens, Robert; Muehlbauer, Michael J.; Kakar, Sanjay; Bass, Nathan M.; Kuusisto, Johanna; Laakso, Markku; Alt, Frederick W.; Newgard, Christopher B.; Farese, Robert V.; Kahn, C. Ronald; Verdin, Eric

doi:10.1016/j.molcel.2011.07.019

Cited by 693 publications

(745 citation statements)

References 78 publications

(111 reference statements)

Supporting

Mentioning

688

Contrasting

Unclassified

Order By: Relevance

“…Thus, SIRT3 may also play a role in mediating islet compensation of insulin resistance, such that only when SIRT3 levels decrease can impaired islet function and type 2 diabetes occur. Increased islet SIRT3 levels are consistent with other studies in skeletal muscle and liver, which reported increases in mitochondrial proteins, including SIRT3, in earlier stages of high-fat feeding [48,49]. We also demonstrated marked reductions in SIRT3 levels in islets isolated from animals that had been fasted for 24 h. This is at odds with findings in liver, where SIRT3 levels increased following a 24 h fast [50,51].…”

Section: Discussionsupporting

confidence: 91%

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

et al. 2013

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 91%

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

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Numerous mitochondrial proteins are subject to reversible Lys acetylation, many of which are directly involved in metabolic homeostasis (Anderson & Hirschey, 2012; Kim et al, 2006). Thus, it is not surprising to observe that hyperacetylation of mitochondrial proteins is often observed in obesity (Hirschey et al., 2011) and chronic alcohol consumption (Shepard, Tuma & Tuma, 2010). Our results further support that mitochondrial protein modification by the acetylation/deacetylation reaction is a key event governing cellular response to ischemic stress.…”

Section: Discussionmentioning

confidence: 99%

Loss of sirtuin 1 and mitofusin 2 contributes to enhanced ischemia/reperfusion injury in aged livers

et al. 2018

View full text Add to dashboard Cite

SummaryIschemia/reperfusion (I/R) injury is a causative factor contributing to morbidity and mortality during liver resection and transplantation. Livers from elderly patients have a poorer recovery from these surgeries, indicating reduced reparative capacity with aging. Mechanisms underlying this age‐mediated hypersensitivity to I/R injury remain poorly understood. Here, we investigated how sirtuin 1 (SIRT1) and mitofusin 2 (MFN2) are affected by I/R in aged livers. Young (3 months) and old (23–26 months) male C57/BL6 mice were subjected to hepatic I/R in vivo. Primary hepatocytes isolated from each age group were also exposed to simulated in vitro I/R. Biochemical, genetic, and imaging analyses were performed to assess cell death, autophagy flux, mitophagy, and mitochondrial function. Compared to young mice, old livers showed accelerated liver injury following mild I/R. Reperfusion of old hepatocytes also showed necrosis, accompanied with defective autophagy, onset of the mitochondrial permeability transition, and mitochondrial dysfunction. Biochemical analysis indicated a near‐complete loss of both SIRT1 and MFN2 after I/R in old hepatocytes, which did not occur in young cells. Overexpression of either SIRT1 or MFN2 alone in old hepatocytes failed to mitigate I/R injury, while co‐overexpression of both proteins promoted autophagy and prevented mitochondrial dysfunction and cell death after reperfusion. Genetic approaches with deletion and point mutants revealed that SIRT1 deacetylated K655 and K662 residues in the C‐terminus of MFN2, leading to autophagy activation. The SIRT1‐MFN2 axis is pivotal during I/R recovery and may be a novel therapeutic target to reduce I/R injury in aged livers.

show abstract

“…In the study by Hirschey and co‐workers (Hirschey et al. 2011), feeding mice a high‐fat diet for 13 weeks reduced liver SIRT3 protein content and significantly increased hepatic mitochondrial protein acetylation as compared to mice fed standard diet. The authors attributed the loss of SIRT3 protein to the reduction in PGC‐1 α , a known regulator of SIRT3 (Kong et al.…”

Section: Discussionmentioning

confidence: 99%

Alterations in fatty acid metabolism and sirtuin signaling characterize early type-2 diabetic hearts of fructose-fed rats

et al. 2017

View full text Add to dashboard Cite

Despite the fact that skeletal muscle insulin resistance is the hallmark of type‐2 diabetes mellitus (T2DM), inflexibility in substrate energy metabolism has been observed in other tissues such as liver, adipose tissue, and heart. In the heart, structural and functional changes ultimately lead to diabetic cardiomyopathy. However, little is known about the early biochemical changes that cause cardiac metabolic dysregulation and dysfunction. We used a dietary model of fructose‐induced T2DM (10% fructose in drinking water for 6 weeks) to study cardiac fatty acid metabolism in early T2DM and related signaling events in order to better understand mechanisms of disease. In early type‐2 diabetic hearts, flux through the fatty acid oxidation pathway was increased as a result of increased cellular uptake (CD36), mitochondrial uptake (CPT1B), as well as increased β‐hydroxyacyl‐CoA dehydrogenase and medium‐chain acyl‐CoA dehydrogenase activities, despite reduced mitochondrial mass. Long‐chain acyl‐CoA dehydrogenase activity was slightly decreased, resulting in the accumulation of long‐chain acylcarnitine species. Cardiac function and overall mitochondrial respiration were unaffected. However, evidence of oxidative stress and subtle changes in cardiolipin content and composition were found in early type‐2 diabetic mitochondria. Finally, we observed decreased activity of SIRT1, a pivotal regulator of fatty acid metabolism, despite increased protein levels. This indicates that the heart is no longer capable of further increasing its capacity for fatty acid oxidation. Along with increased oxidative stress, this may represent one of the earliest signs of dysfunction that will ultimately lead to inflammation and remodeling in the diabetic heart.

show abstract

SIRT3 Deficiency and Mitochondrial Protein Hyperacetylation Accelerate the Development of the Metabolic Syndrome

Cited by 693 publications

References 78 publications

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

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

Loss of sirtuin 1 and mitofusin 2 contributes to enhanced ischemia/reperfusion injury in aged livers

Alterations in fatty acid metabolism and sirtuin signaling characterize early type-2 diabetic hearts of fructose-fed rats

Contact Info

Product

Resources

About