| First Author | Rardin MJ | Year | 2013 |
| Journal | Cell Metab | Volume | 18 |
| Issue | 6 | Pages | 920-33 |
| PubMed ID | 24315375 | Mgi Jnum | J:205910 |
| Mgi Id | MGI:5547422 | Doi | 10.1016/j.cmet.2013.11.013 |
| Citation | Rardin MJ, et al. (2013) SIRT5 regulates the mitochondrial lysine succinylome and metabolic networks. Cell Metab 18(6):920-33 |
| abstractText | 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 beta-oxidation and ketogenesis were significantly hypersuccinylated in Sirt5(-/-) animals. Loss of SIRT5 leads to accumulation of medium- and long-chain acylcarnitines and decreased beta-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. |
