Fisher-Wellman 2019 Cell Rep

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Fisher-Wellman KH, Draper JA, Davidson MT, Williams AS, Narowski TM, Slentz DH, Ilkayeva OR, Stevens RD, Wagner GR, Najjar R, Hirschey MD, Thompson JW, Olson DP, Kelly DP, Koves TR, Grimsrud PA, Muoio DM (2019) Respiratory phenomics across multiple models of protein hyperacylation in cardiac mitochondria reveals a marginal impact on bioenergetics. Cell Rep 26:1557-72.

» PMID: 30726738 Open Access

Fisher-Wellman KH, Draper JA, Davidson MT, Williams AS, Narowski TM, Slentz DH, Ilkayeva OR, Stevens RD, Wagner GR, Najjar R, Hirschey MD, Thompson JW, Olson DP, Kelly DP, Koves TR, Grimsrud PA, Muoio DM (2019) Cell Rep

Abstract: Acyl CoA metabolites derived from the catabolism of carbon fuels can react with lysine residues of mitochondrial proteins, giving rise to a large family of post-translational modifications (PTMs). Mass spectrometry-based detection of thousands of acyl-PTMs scattered throughout the proteome has established a strong link between mitochondrial hyperacylation and cardiometabolic diseases; however, the functional consequences of these modifications remain uncertain. Here, we use a comprehensive respiratory diagnostics platform to evaluate three disparate models of mitochondrial hyperacylation in the mouse heart caused by genetic deletion of malonyl CoA decarboxylase (MCD), SIRT5 demalonylase and desuccinylase, or SIRT3 deacetylase. In each case, elevated acylation is accompanied by marginal respiratory phenotypes. Of the >60 mitochondrial energy fluxes evaluated, the only outcome consistently observed across models is a ∼15% decrease in ATP synthase activity. In sum, the findings suggest that the vast majority of mitochondrial acyl PTMs occur as stochastic events that minimally affect mitochondrial bioenergetics.

Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.

Keywords: ATP synthase, Lysine acylation, Malonylation, Mitochondrial diagnostics Bioblast editor: Plangger M O2k-Network Lab: US TN Nashville Wasserman DH, US NC Durham Koves TR


Labels: MiParea: Respiration, nDNA;cell genetics 


Organism: Mouse  Tissue;cell: Heart, Skeletal muscle  Preparation: Isolated mitochondria  Enzyme: Complex V;ATP synthase  Regulation: ATP production, PCr;Cr  Coupling state: LEAK, OXPHOS, ET  Pathway: F, N, S, Gp  HRR: Oxygraph-2k 

Labels, 2019-02