Journal
MOLECULAR CELL
Volume 13, Issue 6, Pages 805-815Publisher
CELL PRESS
DOI: 10.1016/S1097-2765(04)00124-8
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Funding
- NEI NIH HHS [R01 EY010804, EY10804, R01 EY010804-10] Funding Source: Medline
- NIGMS NIH HHS [GM55766, R01 GM055766] Funding Source: Medline
- NINDS NIH HHS [R01 NS041777, R01 NS041777-06] Funding Source: Medline
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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 1, 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.
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