title: ACAD9, a complex I assembly factor with a moonlighting function in fatty acid oxidation deficiencies.
abstract: Oxidative phosphorylation and fatty acid oxidation are two major metabolic pathways in mitochondria. Acyl-CoA dehydrogenase 9 (ACAD9), an enzyme assumed to play a role in fatty acid oxidation, was recently identified as a factor involved in complex I biogenesis. Here we further investigated the role of ACAD9's enzymatic activity in fatty acid oxidation and complex I biogenesis. We provide evidence indicating that ACAD9 displays enzyme activity in vivo. Knockdown experiments in very-long-chain acyl-CoA dehydrogenase (VLCAD)-deficient fibroblasts revealed that ACAD9 is responsible for the production of C14:1-carnitine from oleate and C12-carnitine from palmitate. These results explain the origin of these obscure acylcarnitines that are used to diagnose VLCAD deficiency in humans. Knockdown of ACAD9 in control fibroblasts did not reveal changes in the acylcarnitine profiles upon fatty acid loading. Next, we investigated whether catalytic activity of ACAD9 was necessary for complex I biogenesis. Catalytically inactive ACAD9 gave partial-to-complete rescue of complex I biogenesis in ACAD9-deficient cells and was incorporated in high-molecular-weight assembly intermediates. Our results underscore the importance of the ACAD9 protein in complex I assembly and suggest that the enzymatic activity is a rudiment of the duplication event.
authors.affiliation: Nijmegen Centre for Mitochondrial Disorders at the Department of Pediatrics, Radboud University Medical Centre, 6500 HB Nijmegen, The Netherlands.
authors.forename: Jessica
authors.initials: J
authors.lastname: Nouws
authors.forename: Heleen
authors.initials: H
authors.lastname: Te Brinke
authors.forename: Leo G
authors.initials: LG
authors.lastname: Nijtmans
authors.forename: Sander M
authors.initials: SM
authors.lastname: Houten
mesh_terms: D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000172:deficiency / Q000378:metabolism; D044944:Acyl-CoA Dehydrogenases / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002331:Carnitine / Q000096:biosynthesis; D002384:Catalysis; D002460:Cell Line; D000080984:Congenital Bone Marrow Failure Syndromes; D042967:Electron Transport Complex I / Q000172:deficiency; D004789:Enzyme Activation; D005227:Fatty Acids / Q000378:metabolism*; D006801:Humans; D008052:Lipid Metabolism, Inborn Errors / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000378:metabolism; D008958:Models, Molecular; D008970:Molecular Weight; D009135:Muscular Diseases / Q000378:metabolism; D009154:Mutation; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D011487:Protein Conformation
chemical_list: D005227:Fatty Acids; D044944:Acyl-CoA Dehydrogenases; D044942:Acyl-CoA Dehydrogenase, Long-Chain; C549517:ACAD9 protein, human; D042967:Electron Transport Complex I; D002331:Carnitine