Mutations in the accessory subunit NDUFB10 result in isolated complex I deficiency and illustrate the critical role of intermembrane space import for complex I holoenzyme assembly
| Autor: | Wallace S. Chick, Elaine B. Spector, Mihret T. Elos, Eric P. Wartchow, Mark A. Lovell, Johan L.K. Van Hove, Kathryn C. Chatfield, Jan Riemer, Alican J. Erdogan, Katherine Gowan, Curtis R. Coughlin, Hua Jiang, Courtney P. O’Rourke, Marisa W. Friederich |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Respiratory chain Mitochondrion Biology medicine.disease_cause Mitochondrial Membrane Transport Proteins NDUFB10 Serine 03 medical and health sciences Oxidoreductase Mitochondrial Precursor Protein Import Complex Proteins Genetics medicine Humans Molecular Biology Genetics (clinical) chemistry.chemical_classification Mutation Electron Transport Complex I Infant Newborn NADH Dehydrogenase General Medicine Articles Infant Nutrition Disorders 030104 developmental biology chemistry Biochemistry Acidosis Lactic Female Intermembrane space Cardiomyopathies Cysteine |
| Zdroj: | Human molecular genetics. 26(4) |
| ISSN: | 1460-2083 |
| Popis: | An infant presented with fatal infantile lactic acidosis and cardiomyopathy, and was found to have profoundly decreased activity of respiratory chain complex I in muscle, heart and liver. Exome sequencing revealed compound heterozygous mutations in NDUFB10, which encodes an accessory subunit located within the PD part of complex I. One mutation resulted in a premature stop codon and absent protein, while the second mutation replaced the highly conserved cysteine 107 with a serine residue. Protein expression of NDUFB10 was decreased in muscle and heart, and less so in the liver and fibroblasts, resulting in the perturbed assembly of the holoenzyme at the 830 kDa stage. NDUFB10 was identified together with three other complex I subunits as a substrate of the intermembrane space oxidoreductase CHCHD4 (also known as Mia40). We found that during its mitochondrial import and maturation NDUFB10 transiently interacts with CHCHD4 and acquires disulfide bonds. The mutation of cysteine residue 107 in NDUFB10 impaired oxidation and efficient mitochondrial accumulation of the protein and resulted in degradation of non-imported precursors. Our findings indicate that mutations in NDUFB10 are a novel cause of complex I deficiency associated with a late stage assembly defect and emphasize the role of intermembrane space proteins for the efficient assembly of complex I. |
| Databáze: | OpenAIRE |
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