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Induction of HIF-2α is dependent on mitochondrial O2 consumption in an O2-sensitive adrenomedullary chromaffin cell line.
- Source :
-
American Journal of Physiology: Cell Physiology . Jun2008, Vol. 294 Issue 6, pC1305-C1312. 8p. 1 Diagram, 6 Graphs. - Publication Year :
- 2008
-
Abstract
- During low O2 (hypoxia), hypoxia-inducible factor (HIF)-α 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-2α 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-2α 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 (p0 cells). Additionally, pharmacological inhibitors of mitochondrial complexes I, III, IV, i.e., rotenone (1 p~M), myxothiazol (1 μM), antimycin A (1 μg/ml), and cyanide (1 mM), blocked HIF-2α 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-2α 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-2α induction. These data suggest that in this O2-sensitive cell line, mitochondrial 02 consumption, rather than changes in ROS, regulates HIF-2α during hypoxia. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 03636143
- Volume :
- 294
- Issue :
- 6
- Database :
- Academic Search Index
- Journal :
- American Journal of Physiology: Cell Physiology
- Publication Type :
- Academic Journal
- Accession number :
- 33182203
- Full Text :
- https://doi.org/10.1152/ajpcell.00007.2008