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
Manisha Vaish
Burke Neurological Institute, White Plains, New York, United States; Pandemic Response Lab, New York, United States
Saravanan S Karuppagounder
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
Irina Gazaryan
Department of Anatomy and Cell Biology, New York Medical College, New York, United States
John W Cave
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
Anatoly A Starkov
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
Elizabeth T Anderson
Institute for Biotechnology, Cornell University, Ithaca, 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
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.
