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Cell Rep. 2019 Feb 5;26(6):1557-1572.e8. doi: 10.1016/j.celrep.2019.01.057.

Respiratory Phenomics across Multiple Models of Protein Hyperacylation in Cardiac Mitochondria Reveals a Marginal Impact on Bioenergetics.

Author information

1
Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27701, USA.
2
Cell Signaling Technologies, Danvers, MA 01923, USA.
3
Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27701, USA; Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA; Department of Medicine, Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, NC 27710, USA.
4
Duke Proteomics and Metabolomics Shared Resource, Duke University Medical Center, Durham, NC 27710, USA.
5
Department of Pediatrics, Division of Pediatric Endocrinology, Michigan Medicine, Ann Arbor, MI 48109, USA.
6
Perelman School of Medicine, University of Pennsylvania, PA 19104, USA.
7
Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27701, USA. Electronic address: paul.grimsrud@duke.edu.
8
Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27701, USA; Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA; Department of Medicine, Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: muoio@duke.edu.

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.

KEYWORDS:

ATP synthase; lysine acylation; malonylation; mitochondrial diagnostics

PMID:
30726738
DOI:
10.1016/j.celrep.2019.01.057
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