Protective effects of ETC complex III and cytochrome c against hydrogen peroxide-induced apoptosis in yeast

Abstract

In mammals, the mitochondrial electron transfer components (ETC) complex III and cytochrome c (cyt c) play essential roles in reactive oxygen species (ROS)-induced apoptosis. However, in yeast, the functions of cyt c and other ETC components remain unclear. In this study, three ETC-defective yeast mutants qcr7Δ, cyc1Δcyc7Δ, and cox12Δ, lacking cyt c oxidoreductase (complex III), cyt c, and cyt c oxidase (complex IV), respectively, were used to test the roles of these proteins in the response of cells to hydrogen peroxide (H2O2). Mutants qcr7Δ and cyc1Δcyc7Δ displayed greater H2O2 sensitivity than the wild-type or cox12Δ mutant. Consistent with this, qcr7Δ and cyc1Δcyc7Δ produced higher ROS levels, displayed derepressed expression of the proapoptotic genes AIF1, NUC1, and NMA111, but not YCA1, at the mRNA level, and were more vulnerable to H2O2-induced apoptosis. Interestingly, mutants lacking these proapoptotic genes displayed enhanced H2O2 tolerance, but unaffected ROS accumulation. Furthermore, the overexpression of antiapoptotic genes (Bcl-2, Ced-9, AtBI-1, and PpBI-1) reduced the levels of AIF1, NUC1, and NMA111 mRNAs, and reduced H2O2-induced cell death. Our findings identify two ETC components as early-inhibitory members of the ROS-mediated apoptotic pathway, suggesting their essential roles in metabolizing H2O2, probably by providing reduced cyt c, allowing cyt c peroxidase to remove H2O2 from the cells.