title: OXPHOS mutations and neurodegeneration.
abstract: Mitochondrial oxidative phosphorylation (OXPHOS) sustains organelle function and plays a central role in cellular energy metabolism. The OXPHOS system consists of 5 multisubunit complexes (CI-CV) that are built up of 92 different structural proteins encoded by the nuclear (nDNA) and mitochondrial DNA (mtDNA). Biogenesis of a functional OXPHOS system further requires the assistance of nDNA-encoded OXPHOS assembly factors, of which 35 are currently identified. In humans, mutations in both structural and assembly genes and in genes involved in mtDNA maintenance, replication, transcription, and translation induce 'primary' OXPHOS disorders that are associated with neurodegenerative diseases including Leigh syndrome (LS), which is probably the most classical OXPHOS disease during early childhood. Here, we present the current insights regarding function, biogenesis, regulation, and supramolecular architecture of the OXPHOS system, as well as its genetic origin. Next, we provide an inventory of OXPHOS structural and assembly genes which, when mutated, induce human neurodegenerative disorders. Finally, we discuss the consequences of mutations in OXPHOS structural and assembly genes at the single cell level and how this information has advanced our understanding of the role of OXPHOS dysfunction in neurodegeneration.
authors.affiliation: Department of Biochemistry, Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands. w.koopman@ncmls.ru.nl
authors.forename: Werner J H
authors.initials: WJ
authors.lastname: Koopman
authors.forename: Felix
authors.initials: F
authors.lastname: Distelmaier
authors.forename: Jan A M
authors.initials: JA
authors.lastname: Smeitink
authors.forename: Peter H G M
authors.initials: PH
authors.lastname: Willems
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics*; D006801:Humans; D007888:Leigh Disease / Q000235:genetics; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D008958:Models, Molecular; D009097:Multienzyme Complexes / Q000235:genetics* / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D019636:Neurodegenerative Diseases / Q000235:genetics*; D010085:Oxidative Phosphorylation
chemical_list: D004272:DNA, Mitochondrial; D009097:Multienzyme Complexes