Acyl-CoA dehydrogenase 9 is required for the biogenesis of oxidative phosphorylation complex I

Jessica Nouws; Leo Nijtmans; Sander M Houten; Mariël van den Brand; Martijn Huynen; Hanka Venselaar; Saskia Hoefs; Jolein Gloerich; Jonathan Kronick; Timothy Hutchin; Peter Willems; Richard Rodenburg; Ronald Wanders; Lambert van den Heuvel; Jan Smeitink; Rutger O Vogel

doi:10.1016/j.cmet.2010.08.002

Acyl-CoA dehydrogenase 9 is required for the biogenesis of oxidative phosphorylation complex I

Cell Metab. 2010 Sep 8;12(3):283-94. doi: 10.1016/j.cmet.2010.08.002.

Authors

Jessica Nouws¹, Leo Nijtmans, Sander M Houten, Mariël van den Brand, Martijn Huynen, Hanka Venselaar, Saskia Hoefs, Jolein Gloerich, Jonathan Kronick, Timothy Hutchin, Peter Willems, Richard Rodenburg, Ronald Wanders, Lambert van den Heuvel, Jan Smeitink, Rutger O Vogel

Affiliation

¹ Nijmegen Centre for Mitochondrial Disorders at the Department of Pediatrics, Radboud University Nijmegen Medical Centre, The Netherlands.

PMID: 20816094
DOI: 10.1016/j.cmet.2010.08.002

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acyl-CoA Dehydrogenase, Long-Chain / chemistry
Acyl-CoA Dehydrogenase, Long-Chain / classification
Acyl-CoA Dehydrogenase, Long-Chain / genetics
Acyl-CoA Dehydrogenase, Long-Chain / metabolism
Acyl-CoA Dehydrogenases / chemistry
Acyl-CoA Dehydrogenases / classification
Acyl-CoA Dehydrogenases / genetics
Acyl-CoA Dehydrogenases / metabolism*
Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism
Amino Acid Sequence
Animals
Cells, Cultured
Electron Transport Complex I / biosynthesis*
Fatty Acids / metabolism
Female
Fibroblasts / cytology
Fibroblasts / physiology
Humans
Infant
Male
Mitochondria / metabolism
Models, Molecular
Molecular Sequence Data
Mutation
NADH Dehydrogenase / genetics
NADH Dehydrogenase / metabolism
Oxidation-Reduction
Oxidative Phosphorylation*
Phylogeny
Pregnancy
Protein Structure, Tertiary
RNA Interference
Sequence Analysis
Sequence Analysis, DNA

Substances

Adaptor Proteins, Signal Transducing
Ecsit protein, human
Fatty Acids
Acyl-CoA Dehydrogenases
Acyl-CoA Dehydrogenase, Long-Chain
ACAD9 protein, human
NADH Dehydrogenase
Electron Transport Complex I
NDUFAF1 protein, human