title: The Acetyl Group Buffering Action of Carnitine Acetyltransferase Offsets Macronutrient-Induced Lysine Acetylation of Mitochondrial Proteins.
abstract: Lysine acetylation (AcK), a posttranslational modification wherein a two-carbon acetyl group binds covalently to a lysine residue, occurs prominently on mitochondrial proteins and has been linked to metabolic dysfunction. An emergent theory suggests mitochondrial AcK occurs via mass action rather than targeted catalysis. To test this hypothesis, we performed mass spectrometry-based acetylproteomic analyses of quadriceps muscles from mice with skeletal muscle-specific deficiency of carnitine acetyltransferase (CrAT), an enzyme that buffers the mitochondrial acetyl-CoA pool by converting short-chain acyl-CoAs to their membrane permeant acylcarnitine counterparts. CrAT deficiency increased tissue acetyl-CoA levels and susceptibility to diet-induced AcK of broad-ranging mitochondrial proteins, coincident with diminished whole body glucose control. Sub-compartment acetylproteome analyses of muscles from obese mice and humans showed remarkable overrepresentation of mitochondrial matrix proteins. These findings reveal roles for CrAT and L-carnitine in modulating the muscle acetylproteome and provide strong experimental evidence favoring the nonenzymatic carbon pressure model of mitochondrial AcK.
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Duke University, Durham, NC 27701, USA.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Davies
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Duke University, Durham, NC 27701, USA.
authors.forename: Lilja
authors.initials: L
authors.lastname: Kjalarsdottir
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27701, USA; Proteomics and Metabolomics Shared Resource, Duke University, Durham, NC 27701, USA.
authors.forename: J Will
authors.initials: JW
authors.lastname: Thompson
authors.affiliation: Proteomics and Metabolomics Shared Resource, Duke University, Durham, NC 27701, USA.
authors.forename: Laura G
authors.initials: LG
authors.lastname: Dubois
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Duke University, Durham, NC 27701, USA.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Stevens
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Duke University, Durham, NC 27701, USA.
authors.forename: Olga R
authors.initials: OR
authors.lastname: Ilkayeva
authors.affiliation: CV and Metabolic Diseases (CVMED), a Pfizer Research Unit, Cambridge, MA 02139, USA.
authors.forename: M Julia
authors.initials: MJ
authors.lastname: Brosnan
authors.affiliation: CV and Metabolic Diseases (CVMED), a Pfizer Research Unit, Cambridge, MA 02139, USA.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Rolph
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Duke University, Durham, NC 27701, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Grimsrud
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Duke University, Durham, NC 27701, USA; Department of Medicine, Duke University, Durham, NC 27701, USA; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27701, USA. Electronic address: muoio@duke.edu.
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Muoio
mesh_terms: D000107:Acetylation; D000818:Animals; D002332:Carnitine O-Acetyltransferase / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D051379:Mice; D024101:Mitochondrial Proteins / Q000378:metabolism*
chemical_list: D024101:Mitochondrial Proteins; D002332:Carnitine O-Acetyltransferase; D008239:Lysine