The Role Of SENP1-SIRT3 Axis In Regulation Of Mitochondrial Metabolic Adaption During Metabolic Stress

Conjugation of SUMO(small ubiquitin-like modifier)to proteins is a major regulator of protein function that plays an important role in a wide range of cellular processes.SUMOylated proteins are found throughout the cell,however,whether SUMOylation could regulate proteins inside mitochondria as well as mitochondrial metabolism are largely unknown.The activity of numerous metabolic enzymes in mitochondria is subject to reversible acetylation in response to various physiological conditions,with most of reports indicate that acetylation of mitochondrial enzymes is an inhibitory mark.SIRT3 is the major member with robust deacetylation activity among the three sirtuins family proteins that reside in the mitochondria.Notablely,lots of metabolic enzymes are deacetylated by SIRT3,which reverses the inhibitory effect of acetylation,resulting in enhanced metabolism,such as fatty acid ?-oxidation,ketone body synthesis and TCA cycle.It is well recognized that Sirt3 expression is induced by fasting and chronic caloric restriction,whether SIRT3 enzyme activity could be regulated by post-translational modifications under nutrition conditions still remains unclear.Here we report that SUMOylation acts as a novel regulator on SIRT3 deacetylation activity.Covalent attachment of SUMO protein to SIRT3 blocks the interaction with SIRT3 substrates,leading to restricted deacetylation activity.In contrast,SUMOylation deficiency activates SIRT3 deacetylation of metabolic enzymes to promote fatty acid ?-oxidation and energy generation.Moreover,SENP1 is essential for SIRT3 deSUMOylation in mitochondria.We found that SENP1 could locate in mitochondria matrix though SENP1 was thought to be a nuclear protein previously.During fasting SENP1 quickly accumulates in mitochondria and deSUMOylates SIRT3 for SIRT3 activation,which occurs much rapider than the modulation of Sirt3 expression.Therefore,mutation of SENP1 or SIRT3 reduces the mitochondrial metabolic adaption in respond to fasting.Interestingly,we found that SENP1 is an acetylated protein and can be deacetylated specifically on two sites by SIR3 in mitochondria.Acetylation inhibits SENP1 deSUMOylation activity on SIRT3,thus resulting in elevated acetylation levels of SIR3 substrates.Our study reveals a positive feedback between SENP1 acetylation and SIRT3 SUMOylation regulats mitochondrial metabolism under caloric restriction.