Partial uncoupling of the mitochondrial membrane by a heterozygous null mutation in the gene encoding the gamma- or delta-subunit of the yeast mitochondrial ATPase.

Prior genetic studies indicated that the yeast mitochondrial ATP synthase can be assembled into enzyme complexes devoid of the gamma-, delta-, or epsilon-subunits (Lai-Zhang, J., Xiao, Y., and Mueller, D. M. (1999) EMBO J. 18, 58-64). These subunit-deficient complexes were postulated to uncouple the mitochondrial membrane thereby causing negative cellular phenotypes. This study provides biochemical and additional genetic data that support this hypothesis. The genetic data indicate that in a diploid cell, a heterozygous deletion mutation in the gene encoding the gamma- or delta-subunit of the ATPase is semidominant negative due to a decrease in the gene number from 2 to 1. However, the heterozygous atp2Delta mutation is epistatic to the heterozygous mutation in the gene encoding gamma or delta, suggesting that the semidominant negative effect is because of a gain of activity in the cells. Biochemical studies using mitochondria isolated from the yeast strains that are heterozygous for a mutation in gamma or delta indicate that the mitochondria are partially uncoupled. These results support the hypothesis that the negative phenotypes are caused by the formation of a gamma- or delta-less ATP synthase complex that is uncoupled.