SENP1-Sirt3 Signaling Controls Mitochondrial Protein Acetylation and Metabolism

Sirt3, as a major mitochondrial nicotinamide adenine dinucleotide (NAD)-dependent deacetylase, is required for mitochondrial metabolic adaption to various stresses. However, how to regulate Sirt3 activity responding to metabolic stress remains largely unknown. Here, we report Sirt3 as a SUMOylated protein in mitochondria. SUMOylation suppresses Sirt3 catalytic activity. SUMOylation-deficient Sirt3 shows elevated deacetylation on mitochondrial proteins and increased fatty acid oxidation. During fasting, SUMO-specific protease SENP1 is accumulated in mitochondria and quickly de-SUMOylates and activates Sirt3. SENP1 deficiency results in hyper-SUMOylation of Sirt3 and hyper-acetylation of mitochondrial proteins, which reduces mitochondrial metabolic adaption responding to fasting. Furthermore, we find that fasting induces SENP1 translocation into mitochondria to activate Sirt3. The studies on mice show that Sirt3 SUMOylation mutation reduces fat mass and antagonizes high-fat diet (HFD)-induced obesity via increasing oxidative phosphorylation and energy expenditure. Our results reveal that SENP1-Sirt3 signaling modulates Sirt3 activation and mitochondrial metabolism during metabolic stress. [Display omitted] •Sirt3 SUMOylation suppresses its catalytic activity in mitochondria•Fasting induces SENP1 translocation into mitochondria to de-SUMOylate Sirt3•The SENP1-Sirt3 axis promotes fatty acid oxidation and energy production•Sirt3 SUMOylation mutation antagonizes HFD-induced obesity via energy expenditure Wang et al. find that SENP1-mediated de-SUMOylation of Sirt3 in mitochondria regulates mitochondrial metabolism responding to fasting and preventing HFD-induced obesity.