Respiratory complex III is required to maintain complex I in mammalian mitochondria.
A puzzling observation in patients with oxidative phosphorylation (OXPHOS) deficiencies is the presence of combined enzyme complex defects associated with a genetic alteration in only one protein-coding gene. In particular, mutations in the mtDNA encoded cytochrome b gene are associated either with combined complex I+III deficiency or with only complex III deficiency. We have reproduced the combined complex I+III defect in mouse and human cultured cell models harboring cytochrome b mutations. In both, complex III assembly is impeded and causes a severe reduction in the amount of complex I, not observed when complex III activity was pharmacologically inhibited. Metabolic labeling in mouse cells revealed that complex I was assembled, although its stability was severely hampered. Conversely, complex III stability was not influenced by the absence of complex I. This structural dependence among complexes I and III was confirmed in a muscle biopsy of a patient harboring a nonsense cytochrome b mutation.
Acín-Pérez
Rebeca
R
Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, Miguel Servet, 177, Zaragoza 50013, Spain.
Bayona-Bafaluy
María Pilar
MP
Fernández-Silva
Patricio
P
Moreno-Loshuertos
Raquel
R
Pérez-Martos
Acisclo
A
Bruno
Claudio
C
Moraes
Carlos T
CT
Enríquez
José A
JA
D000818:Animals; D002478:Cells, Cultured; D002999:Clone Cells; D018389:Codon, Nonsense; D045303:Cytochromes b / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D014450:Electron Transport Complex III / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007739:L Cells; D008322:Mammals; D051379:Mice; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics*; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D010085:Oxidative Phosphorylation
D018389:Codon, Nonsense; D004272:DNA, Mitochondrial; D045303:Cytochromes b; D014450:Electron Transport Complex III