S6-1 Hydrogen sulfide as an oxygen sensor

Abstract

While all vertebrate cells are affected by hypoxia, a few are specifically designed to ensure adequate oxygen delivery throughout the body. These specialized O 2 sensing cells include external-facing chemoreceptors in gills and neonatal airways, arterial chemoreceptor cells in gills, carotid and aortic bodies, adrenal chromaffin cells and vascular smooth muscle. How they detect hypoxia, the O 2 “sensor”, however, remains controversial. I propose that O 2 -dependent metabolism of hydrogen sulfide (H 2 S) is a ubiquitous and ancient O 2 sensor. A variety of physiological and biochemical studies support this hypothesis. (1) The effects of exogenous H 2 S mimic hypoxia in all O 2 sensing tissues. (2) H 2 S production and/or metabolism is inversely coupled to O 2 at physiologically relevant P o 2 s. (3) H 2 S production is O 2 independent whereas, multiple foci of O 2 -dependent H 2 S inactivation are present and many are associated with mitochondria, the purported site of O 2 sensing. (4) H 2 S can be generated from its metabolite, thiosulfate, in mitochondria and this is favored when the mitochondrial matrix becomes more reduced during hypoxia. (5) Compounds that inhibit or augment H 2 S production inhibit and augment hypoxic responses. (6) H 2 S acts upon effector mechanisms known to mediate hypoxic responses. (7) The reciprocal relationship between O 2 and H 2 S has been inexorably intertwined throughout the evolution of eukaryotic cells. Support NSF IOS 1051627.