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SIRT3 and SIRT5 regulate the enzyme activity and cardiolipin binding of very long-chain Acyl-CoA dehydrogenase

Zhang, Y and Bharathi, SS and Rardin, MJ and Uppala, R and Verdin, E and Gibson, BW and Goetzman, ES (2015) SIRT3 and SIRT5 regulate the enzyme activity and cardiolipin binding of very long-chain Acyl-CoA dehydrogenase. PLoS ONE, 10 (3).

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Abstract

SIRT3 and SIRT5 have been shown to regulate mitochondrial fatty acid oxidation but the molecular mechanisms behind the regulation are lacking. Here, we demonstrate that SIRT3 and SIRT5 both target human very long-chain acyl-CoA dehydrogenase (VLCAD), a key fatty acid oxidation enzyme. SIRT3 deacetylates and SIRT5 desuccinylates K299 which serves to stabilize the essential FAD cofactor in the active site. Further, we show that VLCAD binds strongly to cardiolipin and isolated mitochondrial membranes via a domain near the C-terminus containing lysines K482, K492, and K507. Acetylation or succinylation of these residues eliminates binding of VLCAD to cardiolipin. SIRT3 deacetylates K507 while SIRT5 desuccinylates K482, K492, and K507. Sirtuin deacylation of recombinant VLCAD rescues membrane binding. Endogenous VLCAD from SIRT3 and SIRT5 knockout mouse liver shows reduced binding to cardiolipin. Thus, SIRT3 and SIRT5 promote fatty acid oxidation by converging upon VLCAD to promote its activity and membrane localization. Regulation of cardiolipin binding by reversible lysine acylation is a novel mechanism that is predicted to extrapolate to other metabolic proteins that localize to the inner mitochondrial membrane.

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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Zhang, Yyuz29@pitt.eduYUZ29
Bharathi, SSssb26@pitt.eduSSB26
Rardin, MJ
Uppala, Rrru4@pitt.eduRRU4
Verdin, E
Gibson, BW
Goetzman, ESesg5@pitt.eduESG5
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorMakishima, MakotoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 26 March 2015
Date Type: Publication
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Journal or Publication Title: PLoS ONE
Volume: 10
Number: 3
DOI or Unique Handle: 10.1371/journal.pone.0122297
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Pediatrics
Refereed: Yes
Date Deposited: 23 Aug 2016 13:56
Last Modified: 30 Mar 2021 16:55
URI: http://d-scholarship.pitt.edu/id/eprint/28495

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