Role of mitochondria in the regulation of hypoxia-inducible factor-1alpha in the rat carotid body glomus cells.
Hypoxia-inducible factor-1alpha (HIF-1alpha) protein, a heterodimeric transcription factor that regulates transcriptional activation of several genes, is involved in adaptive responses to hypoxia. Earlier, we have reported that in carotid body (CB), the peripheral oxygen sensing organ, HIF-1alpha is up-regulated during hypoxia. One model proposes that an intact mitochondrial respiratory chain is necessary for this regulation of HIF-1alpha. To test this hypothesis in the CB glomus cells, we studied the effect of mitochondrial electron transport chain (ETC) inhibitors: rotenone (complex I; 1 microM), malonate (complex II; 0.5 M), antimycin A (complex III; 1 microg/ml), sodium azide (complex IV; 5 mM), and uncoupler of oxidative phosphorylation: carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP; 1 mM) on HIF-1alpha expression during normoxia and hypoxia. Inhibitors and uncoupler of mitochondrial ETC abrogated hypoxia-induced HIF-1alpha expression in isolated glomus cells significantly (P < 0.001). Effect of rotenone during hypoxia was abolished by succinate (4 mM), a substrate for complex II. Further, HIF-1alpha expression was not altered by any of these mitochondrial inhibitors during normoxia. Taken together, these results strongly indicate that a functional mitochondrial ETC is required for the stabilization of HIF-1alpha, and further the connection between HIF-1alpha and mitochondria in CB oxygen sensing is reiterated.
Baby
Santhosh M
SM
Department of Physiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6085, USA.
Roy
Arijit
A
Lahiri
Sukhamay
S
D000818:Animals; D002344:Carotid Body / Q000166:cytology / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D000860:Hypoxia / Q000378:metabolism; D007473:Ion Channels / Q000378:metabolism; D008322:Mammals; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D028361:Mitochondrial Diseases; D010100:Oxygen / Q000378:metabolism / Q000494:pharmacology; D051381:Rats
D007473:Ion Channels; D010100:Oxygen