HIF1α stabilization in hypoxia is not oxidant-initiated

eLife

Anatoly A Starkov¹  Saravanan S Karuppagounder²  Amit Kumar²  John W Cave²  Rajiv R Ratan²  Manisha Vaish³  Irina Gazaryan⁴  John T Pinto⁵  Austin M Rountree⁶  Ian R Sweet⁶  Wang Wang⁷  Sheng Zhang⁸  Elizabeth T Anderson⁸ 

[1] Brain and Mind Research Institute, Weill Medical College of Cornell University, New York, United States;Department of Neurology, Weill Medical College of Cornell University, New York, United States;Burke Neurological Institute, White Plains, New York, United States;Brain and Mind Research Institute, Weill Medical College of Cornell University, New York, United States;Department of Neurology, Weill Medical College of Cornell University, New York, United States;Burke Neurological Institute, White Plains, New York, United States;Pandemic Response Lab, New York, United States;Department of Anatomy and Cell Biology, New York Medical College, New York, United States;Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, United States;Department of Medicine, University of Washington, Seattle, United States;Department of Pain and Anesthesiology, University of Washington, Seattle, United States;Institute for Biotechnology, Cornell University, Ithaca, United States;

关键词: hypoxia;    mitochondria;    peroxide;    HIF PHDs;    oxygen;    HIF1α stability;    Other;   

DOI  :  10.7554/eLife.72873

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY