title: SIRT5 regulates the mitochondrial lysine succinylome and metabolic networks.
abstract: 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.
authors: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.
authors: Matthew J
authors: MJ
authors: Rardin
authors: Wenjuan
authors: W
authors: He
authors: Yuya
authors: Y
authors: Nishida
authors: John C
authors: JC
authors: Newman
authors: Chris
authors: C
authors: Carrico
authors: Steven R
authors: SR
authors: Danielson
authors: Ailan
authors: A
authors: Guo
authors: Philipp
authors: P
authors: Gut
authors: Alexandria K
authors: AK
authors: Sahu
authors: Biao
authors: B
authors: Li
authors: Radha
authors: R
authors: Uppala
authors: Mark
authors: M
authors: Fitch
authors: Timothy
authors: T
authors: Riiff
authors: Lei
authors: L
authors: Zhu
authors: Jing
authors: J
authors: Zhou
authors: Daniel
authors: D
authors: Mulhern
authors: Robert D
authors: RD
authors: Stevens
authors: Olga R
authors: OR
authors: Ilkayeva
authors: Christopher B
authors: CB
authors: Newgard
authors: Matthew P
authors: MP
authors: Jacobson
authors: Marc
authors: M
authors: Hellerstein
authors: Eric S
authors: ES
authors: Goetzman
authors: Bradford W
authors: BW
authors: Gibson
authors: Eric
authors: E
authors: Verdin
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D002331:Carnitine / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D006885:Hydroxybutyrates / Q000737:chemistry / Q000378:metabolism; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D007657:Ketone Bodies / Q000096:biosynthesis; D008239:Lysine / Q000031:analogs & derivatives* / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D053858:Metabolic Networks and Pathways; D051379:Mice; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000201:enzymology* / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D009154:Mutation; D010084:Oxidation-Reduction; D037761:Sirtuins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013386:Succinates / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*
chemical_list: D006885:Hydroxybutyrates; D007657:Ketone Bodies; D024101:Mitochondrial Proteins; C542554:SIRT5 protein, mouse; D013386:Succinates; D006904:Hydroxymethylglutaryl-CoA Synthase; D037761:Sirtuins; D008239:Lysine; D002331:Carnitine