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CELLULAR AND MITOCHONDRIAL METABOLISM

Induction of HIF-2 is dependent on mitochondrial O₂ consumption in an O₂-sensitive adrenomedullary chromaffin cell line

Department of Biology, McMaster University, Hamilton, Ontario, Canada

Submitted 8 January 2008 ; accepted in final form 11 March 2008

During low O₂ (hypoxia), hypoxia-inducible factor (HIF)- is stabilized and translocates to the nucleus, where it regulates genes critical for survival and/or adaptation in low O₂. While it appears that mitochondria play a critical role in HIF induction, controversy surrounds the underlying mechanism(s). To address this, we monitored HIF-2 expression and oxygen consumption in an O₂-sensitive immortalized rat adrenomedullary chromaffin (MAH) cell line. Hypoxia (2–8% O₂) caused a concentration- and time-dependent increase in HIF-2 induction, which was blocked in MAH cells with either RNA interference knockdown of the Rieske Fe-S protein, a component of complex III, or knockdown of cytochrome-c oxidase subunit of complex IV, or defective mitochondrial DNA (0 cells). Additionally, pharmacological inhibitors of mitochondrial complexes I, III, IV, i.e., rotenone (1 µM), myxothiazol (1 µM), antimycin A (1 µg/ml), and cyanide (1 mM), blocked HIF-2 induction in control MAH cells. Interestingly, the inhibitory effects of the mitochondrial inhibitors were dependent on O₂ concentration such that at moderate-to-severe hypoxia (6% O₂), HIF-2 induction was blocked by low inhibitor concentrations that were ineffective at more severe hypoxia (2% O₂). Manipulation of the levels of reactive oxygen species (ROS) had no effect on HIF-2 induction. These data suggest that in this O₂-sensitive cell line, mitochondrial O₂ consumption, rather than changes in ROS, regulates HIF-2 during hypoxia.

reactive oxygen species; hypoxia-inducible factor; mitochondrial inhibition; RNA interference

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				C. T. Taylor Mitochondria, oxygen sensing, and the regulation of HIF-2{alpha}. Focus on "Induction of HIF-2{alpha} is dependent on mitochondrial O2 consumption in an O2-sensitive adrenomedullary chromaffin cell line" Am J Physiol Cell Physiol, June 1, 2008; 294(6): C1300 - C1302. [Full Text] [PDF]