Transcriptional regulation of yeast oxidative phosphorylation hypoxic genes by oxidative stress

Aims: Mitochondrial cytochrome c oxidase (COX) subunit 5 and cytochrome c (Cyc) exist in two isoforms, transcriptionally regulated by oxygen in yeast. The gene pair COX5a/CYC1 encodes the normoxic isoforms (Cox5a and iso1-Cyc) and the gene pair COX5b/CYC7 encodes the hypoxic isoforms (Cox5b and iso2-Cyc). Rox1 is a transcriptional repressor of COX5b/CYC7 in normoxia. COX5b is additionally repressed by Ord1. Here, we investigated whether these pathways respond to environmental and mitochondria-generated oxidative stress. Results: The superoxide inducer menadione triggered a significant de-repression of COX5b and CYC7. Hydrogen peroxide elicited milder de-repression effects that were enhanced in the absence of Yap1, a key determinant in oxidative stress resistance. COX5b/CYC7 was also de-repressed in wild-type cells treated with antimycin A, a mitochondrial bc₁ complex inhibitor that increases superoxide production. Exposure to menadione and H₂O₂ enhanced both, Hap1-independent expression of ROX1 and Rox1 steady-state levels without affecting Ord1. However, oxidative stress lowered the occupancy of Rox1 on COX5b and CYC7 promoters, thus inducing their de-repression. Innovation: Reactive oxygen species (ROS)-induced hypoxic gene expression in normoxia involves the oxygen-responding Rox1 transcriptional machinery. Contrary to what occurs in hypoxia, ROS enhances Rox1 accumulation. However, its transcriptional repression capacity is compromised. Conclusion: ROS induce expression of hypoxic COX5b and CYC7 genes through an Ord1- and Hap1-independent mechanism that promotes the release of Rox1 from or limits the access of Rox1 to its hypoxic gene promoter targets. Antioxid. Redox Signal. 19, 1916-1927.