Myxothiazol resistance in human mitochondria.
We have investigated electron transfer activities of respiratory chain complexes in platelet mitochondria of a patient with intermittent ataxia and lactic acidosis who was previously reported to be deficient in the E1 (decarboxylase) component of the pyruvate dehydrogenase complex. Electron transfer from succinate to cytochrome c was normal, but the mitochondria exhibited moderately decreased (63% of control) quinol: cytochrome-c oxidoreductase activity, suggesting a defect in complex III. Consistent with some perturbation in complex III, electron flux through complex III was resistant to inhibition by myxothiazol compared to normal controls. In contrast, titration with antimycin revealed a less abnormal pattern of inhibition. The extreme specificity of myxothiazol binding at or near the quinol oxidase domain of mitochondrial cytochrome b, i.e., b-566, suggests a defect in this region of complex III which may perturb the kinetics or thermodynamics of quinol oxidation in the complex. These data suggest that the patient's illness results from a mutation in the quinol oxidase domain of mitochondrial cytochrome b (b-566).
Parker
W D
WD
University of Colorado School of Medicine, Denver.
Frerman
F
F
Haas
R
R
Parks
J K
JK
D000140:Acidosis, Lactic / Q000097:blood; D000968:Antimycin A / Q000031:analogs & derivatives / Q000494:pharmacology; D001259:Ataxia / Q000201:enzymology*; D001792:Blood Platelets / Q000648:ultrastructure*; D003573:Cytochrome b Group / Q000097:blood / Q000235:genetics; D004351:Drug Resistance; D004578:Electron Spin Resonance Spectroscopy; D004579:Electron Transport / Q000187:drug effects; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors / Q000097:blood* / Q000235:genetics; D003576:Electron Transport Complex IV / Q000097:blood; D006801:Humans; D006873:Hydroquinones / Q000378:metabolism; D008689:Methacrylates; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009154:Mutation; D010084:Oxidation-Reduction; D015325:Pyruvate Dehydrogenase Complex Deficiency Disease / Q000097:blood / Q000235:genetics; D013844:Thiazoles / Q000494:pharmacology
D003573:Cytochrome b Group; D006873:Hydroquinones; D008689:Methacrylates; D013844:Thiazoles; C032456:antimycin; C020730:cytochrome b566; D000968:Antimycin A; C030517:myxothiazol; D003576:Electron Transport Complex IV; D014450:Electron Transport Complex III