SIRT5 regulates the mitochondrial lysine succinylome and metabolic networks.
Reversible posttranslational modifications are emerging as critical regulators of mitochondrial proteins and metabolism. Here, we use a label-free quantitative proteomic approach to characterize the lysine succinylome in liver mitochondria and its regulation by the desuccinylase SIRT5. A total of 1,190 unique sites were identified as succinylated, and 386 sites across 140 proteins representing several metabolic pathways including β-oxidation and ketogenesis were significantly hypersuccinylated in Sirt5(-/-) animals. Loss of SIRT5 leads to accumulation of medium- and long-chain acylcarnitines and decreased β-hydroxybutyrate production in vivo. In addition, we demonstrate that SIRT5 regulates succinylation of the rate-limiting ketogenic enzyme 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) both in vivo and in vitro. Finally, mutation of hypersuccinylated residues K83 and K310 on HMGCS2 to glutamic acid strongly inhibits enzymatic activity. Taken together, these findings establish SIRT5 as a global regulator of lysine succinylation in mitochondria and present a mechanism for inhibition of ketogenesis through HMGCS2.
Rardin, MJ; He, W; Nishida, Y; Newman, JC; Carrico, C; Danielson, SR; Guo, A; Gut, P; Sahu, AK; Li, B; Uppala, R; Fitch, M; Riiff, T; Zhu, L; Zhou, J; Mulhern, D; Stevens, RD; Ilkayeva, OR; Newgard, CB; Jacobson, MP; Hellerstein, M; Goetzman, ES; Gibson, BW; Verdin, E
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