title: 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: Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry and.
authors: Olga
authors: O
authors: Pougovkina
authors: Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry and.
authors: Heleen
authors: H
authors: te Brinke
authors: Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry and.
authors: Rob
authors: R
authors: Ofman
authors: Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry and.
authors: Arno G
authors: AG
authors: van Cruchten
authors: Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry and.
authors: Wim
authors: W
authors: Kulik
authors: Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry and Department of Pediatrics, Emma's Children Hospital, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
authors: Ronald J A
authors: RJ
authors: Wanders
authors: Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry and Department of Pediatrics, Emma's Children Hospital, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
authors: Sander M
authors: SM
authors: Houten
authors: Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry and Department of Pediatrics, Emma's Children Hospital, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands v.c.deboer@amc.uva.nl.
authors: Vincent C J
authors: VC
authors: de Boer
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism*; D000107:Acetylation; D000818:Animals; D015153:Blotting, Western; D002853:Chromatography, Liquid; D004591:Electrophoresis, Polyacrylamide Gel; D005227:Fatty Acids / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D020675:Peroxisomes / Q000378:metabolism; D053719:Tandem Mass Spectrometry
chemical_list: D005227:Fatty Acids; D000105:Acetyl Coenzyme A