Increase in intracellular hydrogen peroxide and upregulation of a nuclear respiratory gene evoked by impairment of mitochondrial electron transfer in human cells

We have investigated an interorganelle communication pathway between the nucleus and mitochondria. We loaded a stress specific to mitochondria of human fibroblast cells by antimycin A (AA), an inhibitor of the mitochondrial cytochrome bc(1) complex. AA inhibited cellular respiration in a dose-dependent manner. When the respiratory capacity was reduced to 50-70% of the original one, mRNA levels of cytochrome c(1) as well as cytochrome b increased at 24 h after AA treatment, resulting in maintenance of the cell viability. In contrast, the cells retaining less than 40% of the original capacity showed no increase in either mRNA level and were targeted for death. Intracellular H2O2 level monitored by the fluorescence of dichlorofluorescein increased within 3 h in both the cases, although this increase was higher in the cells where the mRNA levels increased. An antioxidant N-acetylcysteine repressed the increases of not only H2O2 but also cytochrome c(1) mRNA levels. These results suggest that the cells can respond to a limited impairment of electron transfer by promoting expression of nuclear and mitochondrial genes, probably through an H2O2-dependent signaling pathway. (C) 1998 Academic Press.