Characterization of mouse nuclear and mitochondrial mutants with increased resistance to cytochrome b inhibitors.
A series of mouse lines with increased resistance to respiratory inhibitors which block electron transport through the protonmotive cytochrome b of complex III have been isolated in this laboratory. We describe here the isolation of a mutant with increased resistance to HQNO (2-n-heptyl-4-hydroxyquinoline-N-oxide) whose phenotype is due to a nuclear mutation. At the cellular level, there is a severe reduction in respiration with the residual oxygen consumption being resistant to inhibitors of both ubiquinol-cytochrome c oxidoreductase and cytochrome oxidase. At the mitochondrial level, there was a severe derangement in NADH oxidase activity. Electron transport through the succinate oxidase span of the respiratory chain and its coupling to oxidative phosphorylation are also reduced in this nuclear mutant but not to the same extent. It is concluded that the primary defect in the mutant lies within a nuclear gene encoding a component of complex I (NADH-ubiquinol oxidoreductase). In addition, further biochemical characterization of the mitochondrially inherited inhibitor-resistant mutants has demonstrated that they also show significant reductions in the efficiency of energy transduction and in the rate of cytochrome b electron transport.
Howell
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Department of Radiation Therapy, University of Texas Medical Branch, Galveston 77550.
Nalty
M S
MS
D000818:Animals; D001386:Azides / Q000494:pharmacology; D002460:Cell Line; D002467:Cell Nucleus / Q000201:enzymology / Q000378:metabolism; D003573:Cytochrome b Group / Q000037:antagonists & inhibitors* / Q000235:genetics; D004579:Electron Transport / Q000187:drug effects; D006822:Hybrid Cells; D006912:Hydroxyquinolines / Q000494:pharmacology; D051379:Mice; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism; D009154:Mutation; D013384:Succinate Cytochrome c Oxidoreductase / Q000037:antagonists & inhibitors / Q000235:genetics
D001386:Azides; D003573:Cytochrome b Group; D006912:Hydroxyquinolines; C001333:2-(n-heptyl)-4-hydroxyquinoline N-oxide; D013384:Succinate Cytochrome c Oxidoreductase