A molecular chaperone for mitochondrial complex I assembly is mutated in a progressive encephalopathy.
NADH:ubiquinone oxidoreductase (complex I) deficiency is a common cause of mitochondrial oxidative phosphorylation disease. It is associated with a wide range of clinical phenotypes in infants, including Leigh syndrome, cardiomyopathy, and encephalomyopathy. In at least half of patients, enzyme deficiency results from a failure to assemble the holoenzyme complex; however, the molecular chaperones required for assembly of the mammalian enzyme remain unknown. Using whole genome subtraction of yeasts with and without a complex I to generate candidate assembly factors, we identified a paralogue (B17.2L) of the B17.2 structural subunit. We found a null mutation in B17.2L in a patient with a progressive encephalopathy and showed that the associated complex I assembly defect could be completely rescued by retroviral expression of B17.2L in patient fibroblasts. An anti-B17.2L antibody did not associate with the holoenzyme complex but specifically recognized an 830-kDa subassembly in several patients with complex I assembly defects and coimmunoprecipitated a subset of complex I structural subunits from normal human heart mitochondria. These results demonstrate that B17.2L is a bona fide molecular chaperone that is essential for the assembly of complex I and for the normal function of the nervous system.
Ogilvie
Isla
I
Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
Kennaway
Nancy G
NG
Shoubridge
Eric A
EA
D020739:Brain Diseases, Metabolic, Inborn / Q000000981:diagnostic imaging / Q000201:enzymology / Q000235:genetics*; D002478:Cells, Cultured; D002490:Central Nervous System / Q000201:enzymology / Q000473:pathology; D002675:Child, Preschool; D018389:Codon, Nonsense; D042967:Electron Transport Complex I / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics*; D018832:Molecular Chaperones / Q000235:genetics* / Q000378:metabolism; D010085:Oxidative Phosphorylation; D011859:Radiography; D012190:Retroviridae; D014161:Transduction, Genetic / Q000379:methods
D018389:Codon, Nonsense; D018832:Molecular Chaperones; D042967:Electron Transport Complex I