PT  - JOURNAL ARTICLE
AU  - Amit Kumar
AU  - Manisha Vaish
AU  - Saravanan S. Karuppagounder
AU  - Irina Gazaryan
AU  - John W. Cave
AU  - Anatoly A. Starkov
AU  - Elizabeth T. Anderson
AU  - Sheng Zhang
AU  - John T. Pinto
AU  - Austin Rountree
AU  - Wang Wang
AU  - Ian R. Sweet
AU  - Rajiv R. Ratan
TI  - Oxidants are dispensable for HIF1α stability in hypoxia
AID  - 10.1101/2020.05.05.079681
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.05.05.079681
4099  - http://biorxiv.org/content/early/2020/10/25/2020.05.05.079681.short
4100  - http://biorxiv.org/content/early/2020/10/25/2020.05.05.079681.full
AB  - Hypoxic adaptation mediated by HIF transcription factors has been shown to require mitochondria. Current models suggest that mitochondria regulate oxygen sensor (HIF prolyl hydroxylase) activity and HIF1α stability during hypoxia by either increasing mitochondrial peroxide as a second messenger or by serving as oxygen consumers that enhance the kinetics of cytoplasmic oxygen reduction. Here, we address the role of mitochondrial peroxide specifically in regulating HIF1α stability. We use state-of-the-art tools to evaluate the role of peroxide and other reactive oxygen species (ROS) in regulating HIF1α stability. We show that antioxidant enzymes are not homeostatically induced nor are peroxide levels increased in hypoxia. Forced expression of diverse antioxidant enzymes, all of which diminish peroxide, had disparate effects on HIF1α protein stability. Reduction of lipid peroxides by glutathione peroxidase-4 or superoxide by mitochondrial SOD failed to influence HIF1α protein stability. These data showed that mitochondrial, cytosolic and lipid ROS are dispensable for HIF1α stability and should affirm therapeutic efforts to activate the HIF pathway in disease states by HIF prolyl hydroxylase inhibition.Competing Interest StatementThe authors have declared no competing interest.