SIRT5 regulates the mitochondrial lysine succinylome and metabolic networks
By Matthew J. Rardin, Wenjuan He, Y. Nishida, John C. Newman, C. Carrico, S. Danielson, A. Guo, P. Gut, A. Sahu, Biao Li and 14 more. Cell Metabolism, 2013
678 citations recorded by the source corpus.
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 1190 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.
Subfields: Epidemiology, Geriatrics and Gerontology, Physiology
View Paper: https://www.semanticscholar.org/paper/4430096eedc25e33e517a7a4fa8d99d10f2e7e2b
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In Physiology
Citations in the corpus
- Histone Modifications and Cancer. (2016, background): “…breast cancer SIRT4 III GDH (ADP-ribosylation) Underexpressed in AML blasts SIRT5 III Cytochrome c, CPS1 HMGCS2, and SOD1 (desuccinylation) (Rardin et al. 2013) SIRT5 suggested to desuccinylate and activate SOD1, inhibiting lung tumor growth in vitro (Lin et al. 2013) SIRT6 III H3K9, H3K56…”
- Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics (2017, background): “HMGCS2 activity is allosterically inhibited by succinyl-CoA and lysine residue succinylation (Arias et al., 1995; Hegardt, 1999; Lowe and Tubbs, 1985; Quant et al., 1990; Rardin et al., 2013; Reed et al., 1975; Thumelin et al., 1993).”