Bioenergetics of red blood cells regulated by hydrogen sulfide

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Bioenergetics is the process whereby energy is generated from glycolysis in eukaryotes in the form of ATP. Anaerobic glycolysis occurs in the cytosol, which converts glucose to lactate while generating 2 ATP per glucose molecule. Aerobic glycolysis is completed in the mitochondrion, producing 30-32 ATP from each molecule of glucose via oxidative phosphorylation (OXPHOS). The regulation of bioenergetics depends on whether mitochondria are present, glucose and oxygen levels, and the effects of other endogenous regulators. Hydrogen sulfide (H2S) is one important endogenous factor. Its production and biological importance in eukaryotes have been known for more than a decade. The research supported by my previous NSERC Discovery grants has demonstrated, confirmed by numerous reports from other researchers, that H2S is generated in both the cytosol and mitochondrion in mammalian cells and that H2S regulates mitochondrial ATP production, promotes mitochondrial biogenesis, and affects cell viability. Mature mammalian red blood cells (RBCs) do not possess mitochondria and their bioenergetics relies on anaerobic glycolysis whereas avian RBCs have functional mitochondria and their bioenergetics involves both anaerobic glycolysis and OXPHOS. Whether mammalian and avian RBCs use the same or different mechanisms to produce H2S is unknown. The roles of H2S in the regulation of bioenergetics as well as viability of RBCs, in the presence or absence of mitochondria, have not been studied. We hypothesize that H2S differentially regulates anaerobic glycolysis and OXPHOS in mammalian and avian RBCs, exerting different functional impacts on the function and survival of these cells. The objectives of this program are to examine, in mitochondrion-free mouse RBCs and mitochondrion-containing chicken RBCs, 1) the production of endogenous H2S and its regulation; 2) the effects of H2S on anaerobic glycolysis and OXPHOS and the underlying mechanisms; 3) the impact of H2S-regulated bioenergetics on cellular survival and functions; and 4) the effects of polysulfide on bioenergetics and cell survival in comparison with those of H2S. These short-term objectives align with the long-term objective of my research career, i.e. to elucidate the metabolism and biological importance of gasotransmitters, including H2S, in eukaryotes. The proposed program can help better understand how the bioenergetics of RBCs is regulated by H2S to sustain the lifespan of these cells. New light will be shed on the significance of evolutionary extrusion of the mitochondrion from mammalian RBCs in connection to endogenous H2S metabolism. The knowledge gained will also help to devise H2S-based strategies to specifically regulate bioenergetics-dependent cellular and body functions, such as optimized storage conditions for RBCs in vitro, high altitude adaptation where oxygen supply is limited, or exercise and physical activities.