Universität zu Köln

Friederich, Marisa W., Erdogan, Alican J., Coughlin, Curtis R., II, Elos, Mihret T., Jiang, Hua, O'Rourke, Courtney P., Lovell, Mark A., Wartchow, Eric, Gowan, Katherine, Chatfield, Kathryn C., Chick, Wallace S., Spector, Elaine B., Van Hove, Johan L. K. and Riemer, Jan (2017). 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. Hum. Mol. Genet., 26 (4). S. 702 - 717. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2083

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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 P-D 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Friederich, Marisa W. UNSPECIFIED UNSPECIFIED UNSPECIFIED Erdogan, Alican J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Coughlin, Curtis R., II UNSPECIFIED UNSPECIFIED UNSPECIFIED Elos, Mihret T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Jiang, Hua UNSPECIFIED UNSPECIFIED UNSPECIFIED O'Rourke, Courtney P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lovell, Mark A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wartchow, Eric UNSPECIFIED UNSPECIFIED UNSPECIFIED Gowan, Katherine UNSPECIFIED UNSPECIFIED UNSPECIFIED Chatfield, Kathryn C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Chick, Wallace S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Spector, Elaine B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Van Hove, Johan L. K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Riemer, Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-239698
DOI:	10.1093/hmg/ddw431
Journal or Publication Title:	Hum. Mol. Genet.
Volume:	26
Number:	4
Page Range:	S. 702 - 717
Date:	2017
Publisher:	OXFORD UNIV PRESS
Place of Publication:	OXFORD
ISSN:	1460-2083
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Chemistry > Institute of Biochemistry
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language RESPIRATORY-CHAIN; MITOCHONDRIAL PROTEINS; DISEASE; MIA40; DEFECTS; REVEALS; PHOSPHORYLATION; GLUTATHIONE; DIAGNOSIS; OXIDATION Multiple languages Biochemistry & Molecular Biology; Genetics & Heredity Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/23969