Perspectives on Oxygen Sensing

A priori, one could postulate a variety of mechanisms by which cells might measure O2 concentration

Gregg L Semenza


Scholarcy highlights

  • A priori, one could postulate a variety of mechanisms by which cells might measure O2 concentration
  • In the bacterium Rhizobium meliloti, a two-component signaling system consists of FixL, a hemoprotein kinase that is active in the deoxy state, and FixJ, a transcription factor that is active when phosphorylated by FixL
  • There has been no experimental support for a ligand model, but it remains possible that mammalian O2 sensing involves molecular interactions with one or more hemoproteins
  • HIF-1␣ is a basic-helix-loop-helix-PAS protein and the PAS domain is extensively utilized for O2 and redox sensing in Archaea, Bacteria, and Eucarya, suggesting that HIF-1 activity may be directly affected by changes in O2 concentration
  • The second major contribution is their demonstration of a role for cGMP-dependent protein kinase and/or nitric oxide synthase, using genetic and pharmacologic approaches in a remarkable spectrum of behavioral, cellular, developmental, and survival responses to hypoxia in this organism
  • Can any connections be made between available data from Drosophila and mammalian cells? Analysis of isolated rat liver mitochondria and cultured endothelial cells revealed that as O2 concentration was reduced, the rate of O2 consumption declined, whereas such an effect was not observed in the presence of a NOS inhibitor, suggesting that constitutive low-level mitochondrial production of NO may result in competitive inhibition of cytochrome oxidase at low O2 concentrations
  • The further characterization and cloning of mammalian mitochondrial NOS and analysis of knockout mouse ES cells lacking expression of this or other nitric oxide synthase isoforms may provide additional insights into mechanisms of O2 sensing

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