Mitochondrial protein acetylation is driven by acetyl-CoA from fatty acid oxidation.

Abstract

Mitochondria integrate metabolic networks for maintaining bioenergetic requirements. Deregulation of mitochondrial metabolic networks can lead to mitochondrial dysfunction, which is a common hallmark of many diseases. Reversible post-translational protein acetylation modifications are emerging as critical regulators of mitochondrial function and form a direct link between metabolism and protein function, via the metabolic intermediate acetyl-CoA. Sirtuins catalyze protein deacetylation, but how mitochondrial acetylation is determined is unclear. We report here a mechanism that explains mitochondrial protein acetylation dynamics in vivo. Food withdrawal in mice induces a rapid increase in hepatic protein acetylation. Furthermore, using a novel LC-MS/MS method, we were able to quantify protein acetylation in human fibroblasts. We demonstrate that inducing fatty acid oxidation in fibroblasts increases protein acetylation. Furthermore, we show by using radioactively labeled palmitate that fatty acids are a direct source for mitochondrial protein acetylation. Intriguingly, in a mouse model that resembles human very-long chain acyl-CoA dehydrogenase (VLCAD) deficiency, we demonstrate that upon food-withdrawal, hepatic protein hyperacetylation is absent. This indicates that functional fatty acid oxidation is necessary for protein acetylation to occur in the liver upon food withdrawal. Furthermore, we now demonstrate that protein acetylation is abundant in human liver peroxisomes, an organelle where acetyl-CoA is solely generated by fatty acid oxidation. Our findings provide a mechanism for metabolic control of protein acetylation, which provides insight into the pathophysiogical role of protein acetylation dynamics in fatty acid oxidation disorders and other metabolic diseases associated with mitochondrial dysfunction.

• Authors: Olga Pougovkina, Heleen te Brinke, Rob Ofman, Arno G van Cruchten, Wim Kulik, Ronald J A Wanders, Sander M Houten, Vincent C J de Boer
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 23 Issue 13 Pg. 3513-22 (Jul 01 2014) ISSN: 1460-2083 [Electronic] England
• PMID: 24516071 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Fatty Acids
• Acetyl Coenzyme A

Topics

• Acetyl Coenzyme A (metabolism)
• Acetylation
• Animals
• Blotting, Western
• Chromatography, Liquid
• Electrophoresis, Polyacrylamide Gel
• Fatty Acids (metabolism)
• Fibroblasts (metabolism)
• Humans
• Immunoprecipitation
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Oxidation-Reduction
• Peroxisomes (metabolism)
• Tandem Mass Spectrometry