Mammalian Sir2 Homolog SIRT3 Regulates Global Mitochondrial Lysine Acetylation

TLDR

Sirtuins, including the yeast Sir2 homolog, are known to promote longevity across species, yet studies of the mammalian sirtuin SIRT3 have largely been confined to cell culture. This study aims to determine the in vivo localization and functional role of SIRT3. The authors generated and phenotypically characterized SIRT3 knockout mice to investigate its impact on energy metabolism. SIRT3 is a soluble mitochondrial protein whose loss causes widespread mitochondrial protein hyperacetylation, but SIRT3‑deficient mice remain metabolically normal under basal conditions and retain normal adaptive thermogenesis, indicating that SIRT3 specifically regulates reversible lysine acetylation in mitochondria without overt metabolic defects.

Abstract

Homologs of the Saccharomyces cerevisiae Sir2 protein, sirtuins, promote longevity in many organisms. Studies of the sirtuin SIRT3 have so far been limited to cell culture systems. Here, we investigate the localization and function of SIRT3 in vivo. We show that endogenous mouse SIRT3 is a soluble mitochondrial protein. To address the function and relevance of SIRT3 in the regulation of energy metabolism, we generated and phenotypically characterized SIRT3 knockout mice. SIRT3-deficient animals exhibit striking mitochondrial protein hyperacetylation, suggesting that SIRT3 is a major mitochondrial deacetylase. In contrast, no mitochondrial hyperacetylation was detectable in mice lacking the two other mitochondrial sirtuins, SIRT4 and SIRT5. Surprisingly, despite this biochemical phenotype, SIRT3-deficient mice are metabolically unremarkable under basal conditions and show normal adaptive thermogenesis, a process previously suggested to involve SIRT3. Overall, our results extend the recent finding of lysine acetylation of mitochondrial proteins and demonstrate that SIRT3 has evolved to control reversible lysine acetylation in this organelle.