Obesity and aging diminish sirtuin 1 (SIRT1)-mediated deacetylation of SIRT3, leading to hyperacetylation and decreased activity and stability of SIRT3

Abstract

Sirtuin 3 (SIRT3) deacetylates and regulates many mitochondrial proteins to maintain health, but its functions are depressed in aging and obesity. The best-studied sirtuin, SIRT1, counteracts aging- and obesity-related diseases by deacetylating many proteins, but whether SIRT1 has a role in deacetylating and altering the function of SIRT3 is unknown. Here we show that SIRT3 is reversibly acetylated in the mitochondria and unexpectedly is a target of SIRT1 deacetylation. SIRT3 is hyperacetylated in aged and obese mice, in which SIRT1 activity is low, and SIRT3 acetylation at Lys inhibits its deacetylase activity and promotes protein degradation. Adenovirus-mediated expression of SIRT3 or an acetylation-defective SIRT3-K57R mutant in diet-induced obese mice decreased acetylation of mitochondrial long-chain acyl-CoA dehydrogenase, a known SIRT3 deacetylation target; improved fatty acid β-oxidation; and ameliorated liver steatosis and glucose intolerance. These SIRT3-mediated beneficial effects were not observed with an acetylation-mimic SIRT3-K57Q mutant. Our findings reveal an unexpected mechanism for SIRT3 regulation via SIRT1-mediated deacetylation. Improving mitochondrial SIRT3 functions by inhibiting SIRT3 acetylation may offer a new therapeutic approach for obesity- and aging-related diseases associated with mitochondrial dysfunction.

The nuclear and mitochondrial sirtuins, Sirt6 and Sirt3, regulate each other's activity and protect the heart from developing obesity‐mediated diabetic cardiomyopathy

“…Consistent with our results, increased acetylation of liver mitochondrial proteins has been reported under metabolic stress conditions such as long-term high-fat diet feeding and alcohol consumption (46,56). One recent study has also demonstrated that, in obese and aged mice, liver Sirt3 is acetylated, and that this modification decreased its activity and stability (46). Based on these reports, we take that initial loss of Sirt3 in Pal-treated cardiomyocytes and hearts of HF-HS diet-fed mice results from acetylation of Sirt3 in mitochondria, which could be a first step in the scheme of evolution of diabetic cardiomyopathy.…”

“…It is therefore likely that increased acetylation of mitochondrial proteins, including Sirt3, in diabetic hearts results from excess concentration of acetyl-CoA in mitochondria. Consistent with our results, increased acetylation of liver mitochondrial proteins has been reported under metabolic stress conditions such as long-term high-fat diet feeding and alcohol consumption (46,56). One recent study has also demonstrated that, in obese and aged mice, liver Sirt3 is acetylated, and that this modification decreased its activity and stability (46).…”

“…Pal treatment is likely to increase the concentration of acetyl-CoA in mitochondria and induce nonenzymatic acetylation of mitochondrial proteins (45). A recent study has shown that Sirt3 acetylation decreases its stability (46). To test whether Sirt3 was acetylated after 2 h Quantitation of the Western blots.…”

Oxidative Stress and Space Biology An Organ-Based Approach

“…However, consistent with its cytoprotective function, NRF2 deletion in mice leads to increased sensitivity to radiation, oxidative damage and age-related disease pathologies [105,111]. Specifically, NRF2 knockouts display accelerated heart failure in a myocardial infarct model [112], enhanced retinal degeneration [113,114], bone loss [110,115,116], and deficits in bone and endothelial stem and progenitor cell populations [115,117].…”

“…Moreover, the amount of lactic acid, the glycolysis product, was two orders of magnitude higher in cancer cells than in the normal tissue. When the Warburg effect was discovered, an increased glycolysis in cancer cells under aerobic conditions was misinterpreted as evidence for respiration 112 …”