Does interplay between nitric oxide and mitochondria affect hypoxia-inducible transcription factor-1 activity?
This Commentary discusses recent results from the laboratory of Salvador Moncada (Mateo et al., in this issue of the Biochemical Journal ) that shed light on the interaction of nitric oxide (NO) and the transcription factor hypoxia-inducible factor 1 (HIF-1). Using cells stably transfected with inducible NO synthase (iNOS) under the control of a tetracycline-inducible promoter, they generated a range of NO concentrations and determined how these affected HIF-1alpha stability. HIF-1alpha, a component of the heterodimer HIF-1, is rapidly degraded at high oxygen concentrations, and thus HIF-1 is only active as a transcription factor under hypoxic conditions. The authors found a biphasic effect of NO concentration on HIF-1alpha stability. Close to hypoxia, low NO concentrations destabilized HIF-1alpha by inhibiting mitochondrial respiration, thereby increasing the local oxygen concentration. In contrast, high NO concentrations stabilized HIF-1alpha at both high and low oxygen concentrations by a non-mitochondrial pathway. These data resolve reported discrepancies on the effect of NO on HIF-1alpha stability at low oxygen concentrations and suggest that inhibition of mitochondrial respiration by NO may affect oxygen sensing by HIF-1 in vivo.
Murphy
Michael P
MP
MRC Dunn Human Nutrition Unit, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 2XY, UK. mpm@mrc-dunn.cam.ac.uk
D015687:Cell Hypoxia; D019069:Cell Respiration; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology*; D009569:Nitric Oxide / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014157:Transcription Factors; D009569:Nitric Oxide