Acyl-CoA dehydrogenase 9 is required for the biogenesis of oxidative phosphorylation complex I.
Acyl-CoA dehydrogenase 9 (ACAD9) is a recently identified member of the acyl-CoA dehydrogenase family. It closely resembles very long-chain acyl-CoA dehydrogenase (VLCAD), involved in mitochondrial beta oxidation of long-chain fatty acids. Contrary to its previously proposed involvement in fatty acid oxidation, we describe a role for ACAD9 in oxidative phosphorylation. ACAD9 binds complex I assembly factors NDUFAF1 and Ecsit and is specifically required for the assembly of complex I. Furthermore, ACAD9 mutations result in complex I deficiency and not in disturbed long-chain fatty acid oxidation. This strongly contrasts with its evolutionary ancestor VLCAD, which we show is not required for complex I assembly and clearly plays a role in fatty acid oxidation. Our results demonstrate that two closely related metabolic enzymes have diverged at the root of the vertebrate lineage to function in two separate mitochondrial metabolic pathways and have clinical implications for the diagnosis of complex I deficiency.
Nouws
Jessica
J
Nijmegen Centre for Mitochondrial Disorders at the Department of Pediatrics, Radboud University Nijmegen Medical Centre, The Netherlands.
Nijtmans
Leo
L
Houten
Sander M
SM
van den Brand
Mariël
M
Huynen
Martijn
M
Venselaar
Hanka
H
Hoefs
Saskia
S
Gloerich
Jolein
J
Kronick
Jonathan
J
Hutchin
Timothy
T
Willems
Peter
P
Rodenburg
Richard
R
Wanders
Ronald
R
van den Heuvel
Lambert
L
Smeitink
Jan
J
Vogel
Rutger O
RO
D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000737:chemistry / Q000145:classification / Q000235:genetics / Q000378:metabolism; D044944:Acyl-CoA Dehydrogenases / Q000737:chemistry / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D042967:Electron Transport Complex I / Q000096:biosynthesis*; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D006801:Humans; D007223:Infant; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D009245:NADH Dehydrogenase / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D010802:Phylogeny; D011247:Pregnancy; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D017421:Sequence Analysis; D017422:Sequence Analysis, DNA
D048868:Adaptor Proteins, Signal Transducing; C518657:Ecsit protein, human; D005227:Fatty Acids; D044944:Acyl-CoA Dehydrogenases; D044942:Acyl-CoA Dehydrogenase, Long-Chain; C549517:ACAD9 protein, human; D009245:NADH Dehydrogenase; D042967:Electron Transport Complex I; C506342:NDUFAF1 protein, human