Hydrogen Sulfide as an Oxygen Sensor 2 Kenneth

Eukaryotic cells depend upon oxygen (O2) for their survival and elaborate mechanisms have evolved in multicellular animals, especially vertebrates, to monitor the availability of environmental O2, the efficiency of O2 extraction from the environment, ensure adequate O2 delivery to tissues and even to regulate cellular metabolism when O2 availability is compromised. In vertebrates, specialized O2 “sensing” cells have developed to carry out many of these processes. Although all O2 sensing cells ultimately couple low PO2 (hypoxia) to physiological responses, how these cells actually detect hypoxia, i.e., the “O2 sensor” remains controversial. We have recently proposed that hydrogen sulfide (H2S) through its O2-dependent metabolism is a universal and phylogenetically ancient O2 sensing mechanism. This hypothesis is based on a variety of experimental evidence including; (1) the effects of exogenous H2S mimic hypoxia, (2) H2S production and/or metabolism is biochemically coupled to O2, (3) tissue H2S concentration is inversely related to PO2 at physiologically relevant PO2s, (4) compounds that inhibit or augment H2S production inhibit and augment hypoxic responses, (5) H2S acts upon effector mechanisms known to mediate hypoxic responses, (6) H2S was key to the origin of life and the advent of eukaryotic cells and the reciprocal relationship between O2 and H2S has been inexorably intertwined throughout evolution. The evidence for H2S-mediated O2 sensing is critically examined in this review.