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Cell Chem Biol. 2017 Jun 22;24(6):673-684.e4. doi: 10.1016/j.chembiol.2017.04.009. Epub 2017 May 4.

The Mammalian Malonyl-CoA Synthetase ACSF3 Is Required for Mitochondrial Protein Malonylation and Metabolic Efficiency.

Author information

1
Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Center for Metabolism and Obesity Research, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
2
Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Center for Metabolism and Obesity Research, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
3
Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
4
Department of Environmental Health and Engineering, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
5
Department of Environmental Health and Engineering, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Biology, University of Konstanz 78464, Konstanz, Germany.
6
Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Kennedy Krieger Institute, Baltimore, MD 21205, USA.
7
Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Center for Metabolism and Obesity Research, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: mwolfga1@jhmi.edu.

Abstract

Malonyl-coenzyme A (malonyl-CoA) is a central metabolite in mammalian fatty acid biochemistry generated and utilized in the cytoplasm; however, little is known about noncanonical organelle-specific malonyl-CoA metabolism. Intramitochondrial malonyl-CoA is generated by a malonyl-CoA synthetase, ACSF3, which produces malonyl-CoA from malonate, an endogenous competitive inhibitor of succinate dehydrogenase. To determine the metabolic requirement for mitochondrial malonyl-CoA, ACSF3 knockout (KO) cells were generated by CRISPR/Cas-mediated genome editing. ACSF3 KO cells exhibited elevated malonate and impaired mitochondrial metabolism. Unbiased and targeted metabolomics analysis of KO and control cells in the presence or absence of exogenous malonate revealed metabolic changes dependent on either malonate or malonyl-CoA. While ACSF3 was required for the metabolism and therefore detoxification of malonate, ACSF3-derived malonyl-CoA was specifically required for lysine malonylation of mitochondrial proteins. Together, these data describe an essential role for ACSF3 in dictating the metabolic fate of mitochondrial malonate and malonyl-CoA in mammalian metabolism.

KEYWORDS:

ACSF3; CRISPR/Cas; SIRT5; acetyl-CoA; malonate; malonyl-CoA synthetase; malonylation; metabolomics; mitochondrial metabolism; succinylation

PMID:
28479296
PMCID:
PMC5482780
DOI:
10.1016/j.chembiol.2017.04.009
[Indexed for MEDLINE]
Free PMC Article

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