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SIRT5 Regulates The Mitochondrial Lysine Succinylome And Metabolic Networks.

Matthew J Rardin, Wenjuan He, Y. Nishida, John C Newman, C. Carrico, S. Danielson, A. Guo, P. Gut, A. Sahu, Biao Li, R. Uppala, M. Fitch, T. Riiff, Lei Zhu, J. Zhou, Daniel Mulhern, R. Stevens, O. Ilkayeva, C. Newgard, M. Jacobson, M. Hellerstein, E. Goetzman, B. Gibson, E. Verdin
Published 2013 · Biology, Medicine

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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.
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