title: A Mutation in the Flavin Adenine Dinucleotide-Dependent Oxidoreductase FOXRED1 Results in Cell-Type-Specific Assembly Defects in Oxidative Phosphorylation Complexes I and II.
abstract: Complex I (NADH ubiquinone oxidoreductase) is a large multisubunit enzyme that catalyzes the first step in oxidative phosphorylation (OXPHOS). In mammals, complex I biogenesis occurs in a stepwise manner, a process that requires the participation of several nucleus-encoded accessory proteins. The FAD-dependent oxidoreductase-containing domain 1 (FOXRED1) protein is a complex I assembly factor; however, its specific role in the assembly pathway remains poorly understood. We identified a homozygous missense mutation, c.1308 G→A (p.V421M) in FOXRED1 in a patient who presented with epilepsy and severe psychomotor retardation. A patient myoblast line showed a severe reduction in complex I, associated with the accumulation of subassemblies centered around ∼340 kDa, and a milder decrease in complex II, all of which were rescued by retroviral expression of wild-type FOXRED1. Two additional assembly factors, AIFM1 and ACAD9, coimmunoprecipitated with FOXRED1, and all were associated with a 370-kDa complex I subassembly that, together with a 315-kDa subassembly, forms the 550-kDa subcomplex. Loss of FOXRED1 function prevents efficient formation of this midassembly subcomplex. Although we could not identify subassemblies of complex II, our results establish that FOXRED1 function is both broader than expected, involving the assembly of two flavoprotein-containing OXPHOS complexes, and cell type specific.
authors.affiliation: Montreal Neurological Institute and Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors.forename: Olga
authors.initials: O
authors.lastname: Zurita Rendón
authors.affiliation: Montreal Neurological Institute and Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors.forename: Hana
authors.initials: H
authors.lastname: Antonicka
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Rita
authors.initials: R
authors.lastname: Horvath
authors.affiliation: Montreal Neurological Institute and Department of Human Genetics, McGill University, Montreal, Quebec, Canada eric@ericpc.mni.mcgill.ca.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Shoubridge
mesh_terms: D044944:Acyl-CoA Dehydrogenases / Q000378:metabolism; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D002460:Cell Line; D042967:Electron Transport Complex I / Q000378:metabolism*; D042963:Electron Transport Complex II / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D028361:Mitochondrial Diseases / Q000235:genetics*; D018832:Molecular Chaperones / Q000235:genetics*; D020125:Mutation, Missense; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism; D055503:Protein Multimerization
chemical_list: C494829:AIFM1 protein, human; D051033:Apoptosis Inducing Factor; C556294:FOXRED1 protein, human; D018832:Molecular Chaperones; D044944:Acyl-CoA Dehydrogenases; D042963:Electron Transport Complex II; C549517:ACAD9 protein, human; D042967:Electron Transport Complex I