The site of inhibition of mitochondrial electron transfer by coenzyme Q analogues

Abstract

The effects of 33 quinone derivatives on mitochondrial electron transfer in yeast were examined. Twenty-two of the compounds were also tested for their effects on the growth of yeast cells. Four strong inhibitors of electron transfer were identified: 5- n-undecyl-6-hydroxy-4, 7-dioxobenzothiazole, 7-ω-cyclohexyloctyl-6-hydroxy-5,8-quinolinequinone, 7- n-hexadecyl-mercapto-6-hydroxy-5, 8-quinolinequinone, and 3- n-dodecylmercapto-2-hydroxy-1, 4-naphthoquinone. They inhibit the growth of yeast with ethanol as an energy source, but not when glucose is the energy source. The NADH oxidase activity of isolated mitochondria is 50% inhibited by these quinone derivatives at about 10 −8 m, or 0.5 μmol/g mitochondrial protein; 1000-fold higher concentrations do not affect electron transfer from NADH or succinate to coenzyme Q 2. The effects of the inhibitors on cytochrome spectra indicate that they block electron transfer between cytochromes b and c 1. A possible antagonism between these compounds and coenzyme Q at a site between cytochromes b and C 1 is discussed in terms of Mitchell's “protonmotive Q cycle” hypothesis (Mitchell, P. (1976) J. Theor. Biol. 62, 327–367). 6-β-naphthylmercapto-5-chloro-2,3-dimethoxy-1,4-benzoquinone inhibits electron transfer between succinate and coenzyme Q 2 or phenazine methosulfate, suggesting a site in the succinate-coenzyme Q reductase complex with a different quinone specificity from that of the site in the cytochrome bc 1 complex. Seven of the quinone derivatives inhibit growth on both glucose and ethanol media, indicating that their effect is not the result of inhibition of respiration.