Zhang 2017 J Biol Chem

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Zhang Y, Bharathi SS, Rardin MJ, Lu J, Maringer KV, Sims-Lucas S, Prochownik EV, Gibson BW, Goetzman ES (2017) Lysine desuccinylase SIRT5 binds to cardiolipin and regulates the electron transport chain. J Biol Chem 292:10239-49.

» PMID: 28458255

Zhang Y*, Bharathi SS, Rardin MJ, Lu J, Maringer KV, Sims-Lucas S, Prochownik EV, Gibson BW, Goetzman ES (2017) J Biol Chem

Abstract: SIRT5 is a lysine desuccinylase known to regulate mitochondrial fatty acid oxidation and the urea cycle. Here, SIRT5 was observed to bind to cardiolipin via an amphipathic helix on its N terminus. In vitro, succinyl-CoA was used to succinylate liver mitochondrial membrane proteins. SIRT5 largely reversed the succinyl-CoA-driven lysine succinylation. Quantitative mass spectrometry of SIRT5-treated membrane proteins pointed to the electron transport chain, particularly Complex I, as being highly targeted for desuccinylation by SIRT5. Correspondingly, SIRT5-/- HEK293 cells showed defects in both Complex I- and Complex II-driven respiration. In mouse liver, SIRT5 expression was observed to localize strictly to the periportal hepatocytes. However, homogenates prepared from whole SIRT5-/- liver did show reduced Complex II-driven respiration. The enzymatic activities of Complex II and ATP synthase were also significantly reduced. Three-dimensional modeling of Complex II suggested that several SIRT5-targeted lysine residues lie at the protein: lipid interface of succinate dehydrogenase subunit B. We postulate that succinylation at these sites may disrupt Complex II subunit-subunit interactions and electron transfer. Lastly, SIRT5-/- mice, like humans with Complex II deficiency, were found to have mild lactic acidosis. Our findings suggest that SIRT5 is targeted to protein complexes on the inner mitochondrial membrane via affinity for cardiolipin to promote respiratory chain function.

© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Keywords: Cardiolipin, Electron transport system (ET-pathway), Mitochondria, Protein acylation, Sirtuin Bioblast editor: Kandolf G O2k-Network Lab: US PA Pittsburgh Goetzman ES


Labels: MiParea: Respiration, nDNA;cell genetics 


Organism: Human  Tissue;cell: Liver, HEK  Preparation: Permeabilized cells  Enzyme: Complex I, Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase, Complex V;ATP synthase 

Coupling state: OXPHOS, ET  Pathway: N, NS  HRR: Oxygraph-2k 

Labels, 2017-08 

Clarification

Zhang Y refers to Yuxun Zhang of the University of Pittsburgh and not Yong Zhang