Acyl-CoA Dehydrogenase 9 Is Required for the Biogenesis of Oxidative Phosphorylation Complex I

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.

Lethal Neonatal Progression of Fetal Cardiomegaly Associated to ACAD9 Deficiency

“…Atom contacts and structure validation were checked using the MolProbity server (Davis et al 2007;Chen et al 2010). The p.Arg417Cys mutation was built using the ACAD9 dimer homology model as a template (Nouws et al 2010). The best score rotamer calculated by the mutation tool of SPDBV software (Guex and Peitsch 1997) (http://www.expasy.org/spdbv/) was chosen.…”

“…These results suggest that c.1030-1G>T mutation may induce the production of a truncated protein, which is probably not degraded. An ACAD9 dimer homology model based on the VLCAD crystallographic structure was available (Nouws et al 2010). In this model, it has been reported that in each monomer, Arg417 interacts with Glu413 and that the substitution of this arginine by a lysine residue may have deleterious consequences (Nouws et al 2010).…”

“…An ACAD9 dimer homology model based on the VLCAD crystallographic structure was available (Nouws et al 2010). In this model, it has been reported that in each monomer, Arg417 interacts with Glu413 and that the substitution of this arginine by a lysine residue may have deleterious consequences (Nouws et al 2010). In our case, the substitution of Arg417 by a cysteine residue could also have such consequences, but this substitution in both monomers may have more drastic consequences.…”

“…ACAD9 shares 47% amino acid identity and 65% amino acid similarity with VLCAD, which is encoded by the gene ACADVL (Zhang et al 2002); this could be explained by ACADVL gene duplication. The main difference is a 35-amino-acid stretch within the ACAD9 sequence, which is predicted to form an a helix at the surface of the molecule (Nouws et al 2010). After dimer assembly, these helices could form a hydrophobic cleft interacting with mitochondrial partners different from VLCAD ones.…”

“…ACAD9 deficiency causes decreased levels of NDU-FAF1, Ecsit, and mature complex I (Nouws et al 2010;Mimaki et al 2012). Clinical presentation of ACAD9 deficiency consists either in a severe presentation including Reye-like episodes with acute liver dysfunction, hypertrophic cardiomyopathy, rapidly progressive encephalomyopathy with rhabdomyolysis, and sudden infant death syndrome, or in a milder childhood-onset form consisting in fatigue and vomiting episodes with cognitive dysfunction, or in a pure myopathy with exercise intolerance and lactic acidosis (He et al 2007;Haack et al 2010;Gerards et al 2011;Nouws et al 2014a, b).…”