title: Complex I disorders: causes, mechanisms, and development of treatment strategies at the cellular level.
abstract: Mitochondrial oxidative phosphorylation (OXPHOS) represents the final step in the conversion of nutrients into cellular energy. Genetic defects in the OXPHOS system have an incidence between 1:5,000 and 1:10,000 live births. Inherited isolated deficiency of the first complex (CI) of this system, a multisubunit assembly of 45 different proteins, occurs most frequently and originates from mutations in either the nuclear DNA, encoding 38 structural subunits and several assembly factors, or the mitochondrial DNA, encoding 7 structural subunits. The deficiency is associated with devastating multisystemic disorders, often affecting the brain, with onset in early childhood. There are currently no rational treatment strategies. Here, we present an overview of the genetic origins and cellular consequences of this deficiency and discuss how these insights might aid future development of treatment strategies.
authors.affiliation: Department of Biochemistry, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Federica
authors.initials: F
authors.lastname: Valsecchi
authors.forename: Werner J H
authors.initials: WJ
authors.lastname: Koopman
authors.forename: Ganesh R
authors.initials: GR
authors.lastname: Manjeri
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Rodenburg
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: D000975:Antioxidants / Q000008:administration & dosage; D002648:Child; D002675:Child, Preschool; D002658:Developmental Disabilities / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy; D018450:Disease Progression; D016503:Drug Delivery Systems; D042967:Electron Transport Complex I / Q000172:deficiency* / Q000235:genetics*; D004734:Energy Metabolism / Q000235:genetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D028361:Mitochondrial Diseases / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy; D009943:Organophosphorus Compounds / Q000008:administration & dosage; D010085:Oxidative Phosphorylation; D010971:Plastoquinone / Q000008:administration & dosage / Q000031:analogs & derivatives; D000077185:Resveratrol; D013267:Stilbenes / Q000008:administration & dosage; D014451:Ubiquinone / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: C532038:10-(6'-plastoquinonyl)decyltriphenylphosphonium; D000975:Antioxidants; D009943:Organophosphorus Compounds; D013267:Stilbenes; D014451:Ubiquinone; C429014:mitoquinone; D042967:Electron Transport Complex I; D010971:Plastoquinone; D000077185:Resveratrol