A molecular chaperone for mitochondrial complex I assembly is mutated in a progressive encephalopathy
Open Access
- 1 October 2005
- journal article
- case report
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 115 (10), 2784-2792
- https://doi.org/10.1172/JCI26020
Abstract
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.This publication has 47 references indexed in Scilit:
- Tracing the Evolution of a Large Protein Complex in the Eukaryotes, NADH:Ubiquinone Oxidoreductase (Complex I)Journal of Molecular Biology, 2005
- Subunit composition of mitochondrial complex I from the yeast Yarrowia lipolyticaBiochimica et Biophysica Acta (BBA) - Bioenergetics, 2004
- Pathological Mutations of the Human NDUFS4 Gene of the 18-kDa (AQDQ) Subunit of Complex I Affect the Expression of the Protein and the Assembly and Function of the ComplexOnline Journal of Public Health Informatics, 2003
- CIA30 complex I assembly factor: a candidate for human complex I deficiency?Human Genetics, 2002
- Cytochrome c oxidase deficiencyAmerican Journal of Medical Genetics, 2001
- Involvement of two novel chaperones in the assembly of mitochondrial NADH:ubiquinone oxidoreductase (complex I)Journal of Molecular Biology, 1998
- Three-dimensional structure of bovine NADH:ubiquinone oxidoreductase (complex I) at 22 å in iceJournal of Molecular Biology, 1998
- Gapped BLAST and PSI-BLAST: a new generation of protein database search programsNucleic Acids Research, 1997
- Modular Evolution of the Respiratory NADH:Ubiquinone Oxidoreductase and the Origin of its ModulesJournal of Theoretical Biology, 1997
- Computational Method to Predict Mitochondrially Imported Proteins and their Targeting SequencesJBIC Journal of Biological Inorganic Chemistry, 1996