A molecular chaperone for mitochondrial complex I assembly is mutated in a progressive encephalopathy

J Clin Invest. 2005 Oct;115(10):2784-92. doi: 10.1172/JCI26020.


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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain Diseases, Metabolic, Inborn / diagnostic imaging
  • Brain Diseases, Metabolic, Inborn / enzymology
  • Brain Diseases, Metabolic, Inborn / genetics*
  • Cells, Cultured
  • Central Nervous System / enzymology
  • Central Nervous System / pathology
  • Child, Preschool
  • Codon, Nonsense*
  • Electron Transport Complex I / deficiency
  • Electron Transport Complex I / genetics*
  • Electron Transport Complex I / metabolism
  • Female
  • Fibroblasts / enzymology
  • Fibroblasts / pathology
  • Genome, Human / genetics*
  • Humans
  • Mitochondria / enzymology
  • Mitochondria / genetics*
  • Molecular Chaperones / genetics*
  • Molecular Chaperones / metabolism
  • Oxidative Phosphorylation
  • Radiography
  • Retroviridae
  • Transduction, Genetic / methods


  • Codon, Nonsense
  • Molecular Chaperones
  • Electron Transport Complex I