Sensing hypoxia by mitochondria: a unifying hypothesis involving S-nitrosation.
CONCLUSIONS
Sudden hypoxia requires a rapid response in tissues with high energy demand. Mitochondria are rapid sensors for a lack of oxygen, but no consistent mechanism for the sensing process and the subsequent counter-regulation has been described.


BACKGROUND
In the present hypothesis review, we suggest an oxygen-sensing mechanism by mitochondria that is initiated at low oxygen tension by electrons from the respiratory chain, leading to the reduction of intracellular nitrite to nitric oxide ((•)NO) that would subsequently compete with oxygen for binding to cytochrome c oxidase. This allows superoxide ((•)O2(-)) formation in hypoxic areas, leading to S-nitrosation and the inhibition of mitochondrial Krebs cycle enzymes. With more formation of (•)O2(-), peroxynitrite is generated and known to damage the connection between the mitochondrial matrix and the outer membrane.


RESULTS
A fundamental question on a regulatory mechanism is its reversibility. Readmission of oxygen and opening of the mitochondrial KATP-channel would allow electrons from glycerol-3-phosphate to selectively reduce the ubiquinone pool to generate (•)O2(-) at both sides of the inner mitochondrial membrane. On the cytosolic side, superoxide is dismutated and will support H2O2/Fe(2+)-dependent transcription processes and on the mitochondrial matrix side, it could lead to the one-electron reduction and reactivation of S-nitrosated proteins.


CONCLUSIONS
It remains to be elucidated up to which stage the herein proposed silencing of mitochondria remains reversible and when irreversible changes that ultimately lead to classical reperfusion injury are initiated.
Department of Biology, University of Konstanz , Konstanz, Germany .
Volker
V
Ullrich
Stefan
S
Schildknecht
D000818:Animals; D003600:Cytosol / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D008928:Mitochondria / Q000502:physiology*; D009566:Nitrates / Q000378:metabolism*; D015538:Nitrosation; D010084:Oxidation-Reduction; D010101:Oxygen Consumption; D015398:Signal Transduction
D009566:Nitrates