HIF1α stabilization in hypoxia is not oxidant-initiated

• Published in: eLife Vol. 10
• Main Authors: Kumar, Amit, Vaish, Manisha, Karuppagounder, Saravanan S, Gazaryan, Irina, Cave, John W, Starkov, Anatoly A, Anderson, Elizabeth T, Zhang, Sheng, Pinto, John T, Rountree, Austin M, Wang, Wang, Sweet, Ian R, Ratan, Rajiv R
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 01.10.2021; eLife Sciences Publications, Ltd
• Subjects: Animals; Antioxidants; Binding sites; Cell Biology; Cell Hypoxia; Enzymes; Experiments; Glutathione peroxidase; HeLa Cells; HIF PHDs; HIF1α stability; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Ischemia; Kinases; Male; Mice; Mitochondria; Mitochondria - metabolism; Neuroblastoma; Neuroscience; Oxidants; Oxygen; Peroxide; Peroxides - metabolism; Protein Stability; Proteins; Rats; Rats, Sprague-Dawley; Signal Transduction; Transcription factors; hypoxia; peroxide; cell biology; HIF PHDs; mitochondria; neuroscience; HIF1α stability; oxygen
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.72873

Hypoxic adaptation mediated by HIF transcription factors requires mitochondria, which have been implicated in regulating HIF1α stability in hypoxia by distinct models that involve consuming oxygen or alternatively converting oxygen into the second messenger peroxide. Here, we use a ratiometric, peroxide reporter, HyPer to evaluate the role of peroxide in regulating HIF1α stability. We show that antioxidant enzymes are neither homeostatically induced nor are peroxide levels increased in hypoxia. Additionally, forced expression of diverse antioxidant enzymes, all of which diminish peroxide, had disparate effects on HIF1α protein stability. Moreover, decrease in lipid peroxides by glutathione peroxidase-4 or superoxide by mitochondrial SOD, failed to influence HIF1α protein stability. These data show that mitochondrial, cytosolic or lipid ROS were not necessary for HIF1α stability, and favor a model where mitochondria contribute to hypoxic adaptation as oxygen consumers.