Transcriptional regulation of yeast oxidative phosphorylation hypoxic genes by oxidative stress.
OBJECTIVE
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.


METHODS
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.


CONCLUSIONS
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.
1 Department of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine , Miami, Florida.
Jingjing
J
Liu
Antoni
A
Barrientos
D003574:Cytochrome c Group / Q000235:genetics / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism; D000860:Hypoxia / Q000235:genetics*; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress / Q000235:genetics; D010100:Oxygen / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000235:genetics* / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
D003574:Cytochrome c Group; C083348:ROX1 protein, S cerevisiae; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; C530067:Cox5b protein, S cerevisiae; D003576:Electron Transport Complex IV; D010100:Oxygen