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,...

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Published in:	Cell metabolism 2013-12, Vol.18 (6), p.920-933
Main Authors:	Rardin, Matthew J., He, Wenjuan, Nishida, Yuya, Newman, John C., Carrico, Chris, Danielson, Steven R., Guo, Ailan, Gut, Philipp, Sahu, Alexandria K., Li, Biao, Uppala, Radha, Fitch, Mark, Riiff, Timothy, Zhu, Lei, Zhou, Jing, Mulhern, Daniel, Stevens, Robert D., Ilkayeva, Olga R., Newgard, Christopher B., Jacobson, Matthew P., Hellerstein, Marc, Goetzman, Eric S., Gibson, Bradford W., Verdin, Eric
Format:	Article
Language:	eng
Subjects:	Amino Acid Motifs Animals Carnitine - chemistry Carnitine - metabolism Cell Line Humans Hydroxybutyrates - chemistry Hydroxybutyrates - metabolism Hydroxymethylglutaryl-CoA Synthase - chemistry Hydroxymethylglutaryl-CoA Synthase - genetics Hydroxymethylglutaryl-CoA Synthase - metabolism Ketone Bodies - biosynthesis Lysine - analogs & derivatives Lysine - analysis Lysine - chemistry Lysine - metabolism Male Metabolic Networks and Pathways Mice Mice, Knockout Mitochondria, Liver - enzymology Mitochondria, Liver - metabolism Mitochondrial Proteins - metabolism Mutation Oxidation-Reduction Sirtuins - deficiency Sirtuins - genetics Sirtuins - metabolism Succinates - analysis Succinates - chemistry Succinates - metabolism
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Summary:	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. [Display omitted] •Liver mitochondrial succinylome is quantified in wild-type and Sirt5−/− mice•386 lysine sites on 140 proteins are hypersuccinylated in Sirt5−/− mouse liver•SIRT5 targets enzymes in fatty acid oxidation and ketone body production•Inhibition of HMGCS2 activity by lysine succinylation at K83 and K310
ISSN:	1550-4131 1932-7420