title: 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.
abstract: 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.
authors.affiliation: Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado, School of Medicine, Aurora, CO, USA.
authors.forename: Marisa W
authors.initials: MW
authors.lastname: Friederich
authors.affiliation: Department of Chemistry, Institute of Biochemistry, University of Cologne, Cologne, Germany.
authors.forename: Alican J
authors.initials: AJ
authors.lastname: Erdogan
authors.affiliation: Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado, School of Medicine, Aurora, CO, USA.
authors.forename: Curtis R
authors.initials: CR
authors.lastname: Coughlin
authors.affiliation: Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado, School of Medicine, Aurora, CO, USA.
authors.forename: Mihret T
authors.initials: MT
authors.lastname: Elos
authors.affiliation: Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado, School of Medicine, Aurora, CO, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado, School of Medicine, Aurora, CO, USA.
authors.forename: Courtney P
authors.initials: CP
authors.lastname: O'Rourke
authors.affiliation: Department of Pathology, University of Colorado, Aurora, CO, USA.|Department of Pathology, Children's Hospital of Colorado, Aurora, CO, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Lovell
authors.affiliation: Department of Pathology, University of Colorado, Aurora, CO, USA.|Department of Pathology, Children's Hospital of Colorado, Aurora, CO, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Wartchow
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado, Aurora, CO, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Gowan
authors.affiliation: Department of Pediatrics, Section of Cardiology, University of Colorado, School of Medicine, Aurora, CO, USA.
authors.forename: Kathryn C
authors.initials: KC
authors.lastname: Chatfield
authors.affiliation: Department of Cell and Developmental Biology, University of Colorado, Aurora, CO, USA.
authors.forename: Wallace S
authors.initials: WS
authors.lastname: Chick
authors.affiliation: Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado, School of Medicine, Aurora, CO, USA.
authors.forename: Elaine B
authors.initials: EB
authors.lastname: Spector
authors.affiliation: Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado, School of Medicine, Aurora, CO, USA.
authors.forename: Johan L K
authors.initials: JLK
authors.lastname: Van Hove
authors.affiliation: Department of Chemistry, Institute of Biochemistry, University of Cologne, Cologne, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Riemer
mesh_terms: D000140:Acidosis, Lactic / Q000201:enzymology / Q000235:genetics; D009202:Cardiomyopathies / Q000151:congenital / Q000201:enzymology; D042967:Electron Transport Complex I / Q000172:deficiency*; D005260:Female; D006801:Humans; D007228:Infant Nutrition Disorders / Q000201:enzymology / Q000235:genetics; D007231:Infant, Newborn; D008297:Male; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D009154:Mutation; D009245:NADH Dehydrogenase / Q000235:genetics / Q000378:metabolism
chemical_list: C507282:CHCHD4 protein, human; D033681:Mitochondrial Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D009245:NADH Dehydrogenase; D042967:Electron Transport Complex I; C579493:NDUFB10 protein, human