hCOA3 stabilizes cytochrome c oxidase 1 (COX1) and promotes cytochrome c oxidase assembly in human mitochondria.
Cytochrome c oxidase (COX) or complex IV of the mitochondrial respiratory chain plays a fundamental role in energy production of aerobic cells. In humans, COX deficiency is the most frequent cause of mitochondrial encephalomyopathies. Human COX is composed of 13 subunits of dual genetic origin, whose assembly requires an increasing number of nuclear-encoded accessory proteins known as assembly factors. Here, we have identified and characterized human CCDC56, an 11.7-kDa mitochondrial transmembrane protein, as a new factor essential for COX biogenesis. CCDC56 shares sequence similarity with the yeast COX assembly factor Coa3 and was termed hCOA3. hCOA3-silenced cells display a severe COX functional alteration owing to a decreased stability of newly synthesized COX1 and an impairment in the holoenzyme assembly process. We show that hCOA3 physically interacts with both the mitochondrial translation machinery and COX structural subunits. We conclude that hCOA3 stabilizes COX1 co-translationally and promotes its assembly with COX partner subunits. Finally, our results identify hCOA3 as a new candidate when screening for genes responsible for mitochondrial diseases associated with COX deficiency.
Departamento de Bioquímica, Universidad Autónoma de Madrid, Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-Consejo Superior de Investigaciones Científicas and Centro de Investigación Biomédica en Red de Enfermedades Raras, 28029 Madrid, Spain; Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), 28029 Madrid, Spain.
Paula
P
Clemente
Departamento de Bioquímica, Universidad Autónoma de Madrid, Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-Consejo Superior de Investigaciones Científicas and Centro de Investigación Biomédica en Red de Enfermedades Raras, 28029 Madrid, Spain.
Susana
S
Peralta
Departamento de Bioquímica, Universidad Autónoma de Madrid, Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-Consejo Superior de Investigaciones Científicas and Centro de Investigación Biomédica en Red de Enfermedades Raras, 28029 Madrid, Spain; Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), 28029 Madrid, Spain.
Alberto
A
Cruz-Bermudez
Departamento de Bioquímica, Universidad Autónoma de Madrid, Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-Consejo Superior de Investigaciones Científicas and Centro de Investigación Biomédica en Red de Enfermedades Raras, 28029 Madrid, Spain; Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), 28029 Madrid, Spain.
Lucía
L
Echevarría
Department of Neurology, University of Miami, Miller School of Medicine, Miami, Florida 33136.
Flavia
F
Fontanesi
Department of Neurology, University of Miami, Miller School of Medicine, Miami, Florida 33136; Department of Biochemistry, University of Miami, Miller School of Medicine, Miami, Florida 33136.
Antoni
A
Barrientos
Departamento de Bioquímica, Universidad Autónoma de Madrid, Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-Consejo Superior de Investigaciones Científicas and Centro de Investigación Biomédica en Red de Enfermedades Raras, 28029 Madrid, Spain; Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), 28029 Madrid, Spain; MITOLAB Consortium P2010/BMD-2402, Comunidad de Madrid, 28029 Madrid, Spain.
Miguel A
MA
Fernandez-Moreno
Departamento de Bioquímica, Universidad Autónoma de Madrid, Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-Consejo Superior de Investigaciones Científicas and Centro de Investigación Biomédica en Red de Enfermedades Raras, 28029 Madrid, Spain; Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), 28029 Madrid, Spain; MITOLAB Consortium P2010/BMD-2402, Comunidad de Madrid, 28029 Madrid, Spain. Electronic address: rafael.garesse@uam.es.
Rafael
R
Garesse
D003576:Electron Transport Complex IV / Q000378:metabolism* / Q000502:physiology; D004795:Enzyme Stability; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000201:enzymology*; D051336:Mitochondrial Membranes / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D055503:Protein Multimerization; D021122:Protein Subunits / Q000378:metabolism / Q000502:physiology; D059748:Proteolysis; D034741:RNA, Small Interfering / Q000235:genetics
D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D021122:Protein Subunits; D034741:RNA, Small Interfering; C581052:hCOA3 protein, human; D003576:Electron Transport Complex IV