SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation

Abstract

Sirtuins are NAD+-dependent protein deacetylases and 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 21,2. Mice lacking both SIRT3 alleles appear phenotypically normal under basal conditions, but show marked hyperacetylation of several mitochondrial proteins3. We report that SIRT3 expression is upregulated during fasting in liver and brown adipose tissues. Livers from mice lacking SIRT3 show higher levels of fatty acid oxidation intermediate products and triglycerides during fasting associated with decreased levels of fatty acid oxidation when compared to wild-type mice. Mass spectrometry analysis of mitochondrial proteins shows that long-chain acyl CoA 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 utilization during fasting.

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

“…In contrast, induction of SIRT3 together with mito‐p53 significantly prevented cell death ( P  <   0.05) (Figs 5B and S1A,B, Supporting information). Previous reports have shown that SIRT3 plays a protective role in diverse stress‐induced cell death (Hagen et al ., 1995; Kim et al ., 2007; Hirschey et al ., 2010). To determine whether SIRT3 prevents mito‐p53‐induced toxicity, mito‐p53 cells were transfected with a control vector, WT SIRT3, or mutant ΔSIRT3 and cells were then stained with Annexin V and propidium iodide (PI).…”

“…Epigenetic changes encompass an array of molecular modifications to both DNA and chromatin, including transcription factors and cofactors. SIRTs (mammalian homolog of silent mating type information regulation 2 homolog in yeast) are a family of epigenetic mediators that play various functions in aging, chromatin integrity, metabolic regulation, and longevity (Kim et al ., 2007; Hirschey et al ., 2010). Among sirtuins, SIRT1 has been mostly widely studied and its level is changed in AD brains (Shi et al ., 2005; Someya et al ., 2010; Kim et al ., 2011).…”

“…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).…”

Overexpression of CYB5R3 and NQO1, two NAD+‐producing enzymes, mimics aspects of caloric restriction

“…HK‐II and PFK are the main rate‐controlling enzymes of glycolytic flux while PDH activity, which catalyzes the conversion of pyruvate to acetyl‐CoA, modulates mitochondrial glucose and fatty acid fluxes. Mitochondrial fatty acid (FA) β‐oxidation is a metabolic feature promoted by CR and exercise that is controlled by PGC‐1α, a member of a family of transcriptional coactivators, and the protein deacetylase SIRT3 (Hirschey et al., 2010; Liang & Ward, 2006). Western blot analysis showed significant accumulation of PGC‐1α and SIRT3 in muscle of RedTg mice compared to Wt controls (Figure 2c,d).…”

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

“…Furthermore, SIRT3 is involved in fatty acid oxidation in the liver (Giralt and Villarroya, 2012). This was supported by evidence in SIRT3-knockout mice demonstrating increased palmitoylcarnitine and triacylglycerols in the liver and various acylcarnitines in the blood (Hallows et al, 2011;Hirschey et al, 2010). SIRT3 is also expressed abundantly in the heart, and its overexpression is protective against cardiac hypertrophy, while SIRT3 depletion enhances susceptibility to hypertrophy (Sundaresan et al, 2009).…”