The control of mitochondrial oxidations by complex III in rat muscle and liver mitochondria. Implications for our understanding of mitochondrial cytopathies in man.

We have studied the control by complex III of both succinate-cytochrome c reductase and of oxidative flux measured polarographically in rat muscle and liver mitochondria using the specific inhibitor, myxothiazol, to induce partial inhibitions of complex III activity. Complex III exerted a low degree of control on electron flux through succinate-cytochrome c reductase, and a 30-50% decrease in complex III activity remained undetected by this assay. However, when overall oxidative flux was measured polarographically there was a considerable difference in the effect of lowered complex III activity on this pathway between rat muscle and liver mitochondria. Small changes in complex III activity (approximately 5% inhibition) in muscle mitochondria caused marked changes in succinate-stimulated respiration, whereas in liver mitochondria complex III had to be inhibited by about 45% before changes in maximum oxidation rates could be detected. These differences between muscle and liver mitochondria occurred despite rat liver mitochondria having at least a 4-fold lower complex III activity. This suggests that when considering the biochemical consequences of defects of the respiratory chain an important factor is the degree to which an individual complex can be lowered before major changes in overall flux occur. In addition, since many patients with respiratory chain disease present with predominantly muscle symptoms, this latter finding suggests that an understanding of the control of mitochondrial oxidations by different tissues may be important when considering the tissue-specific nature of defects of the respiratory chain.