Fig. 9.

Roles of H₂S in the stimulation of cellular bioenergetics in cancer cells. H₂S can serve as a direct electron donor into the mitochondrial electron transport chain at the level of Complex II via SQR (Pathway #1), but also, at low concentrations, it can serve as an electron donor at Complex IV (Pathway #2). H₂S can inhibit mitochondrial cAMP phosphodiesterases (as PDE2A), and thereby stimulate intramitochondrial cAMP-dependent protein kinases, which can phosphorylate and thus further activate the electron transport chain (Pathway #3). In addition, H₂S can sulfhydrate LDH-A, resulting in its activation (Pathway #4). H₂S can also directly stimulate the activity of ATP synthase via the sulfhydration of specific cysteines (Pathway #5). H₂S can regulate mitochondrial dynamics (fusion/fission) to maintain the mitochondrial pool in its most effective state (Pathway #6). H₂S can also increase mitochondrial mass via the stimulation of mitochondrial biogenesis (Pathway #7). Additional mechanisms underlying mitochondrial “stabilization” may be simply related to the general antioxidant role of H₂S (Pathway #8). Another mitochondrial protective mechanism is related to the stimulation of mitochondrial DNA repair (Pathway #12). H₂S may also support the cancer cell metabolism via the stimulation of glycolysis, in part through GAPDH and PKM2 sulfhydration and their consequent activation (Pathway #9). H₂S may also stimulate the uptake of glucose and its utilization (Pathway #10), and lipid uptake and its utilization (Pathway #11) into the cells.