mTORC1-Sch9 regulates hydrogen sulfide production through the transsulfuration pathway.

Endogenous hydrogen sulfide mediates anti-aging benefits of dietary restriction (DR). However, it is unclear how HS production is regulated by pathways related to DR. Due to the importance of mTORC1 pathway in DR, we investigated the effects of Sch9, a yeast homolog of mammalian S6K1 and a major substrate of mTORC1 on HS production in yeast . We found that inhibition of the mTORC1-Sch9 pathway by deletion, rapamycin or myriocin treatment resulted in a dramatic decrease in HS production. Although deficiency of did not alter the intracellular level of methionine, the intracellular level of cysteine increased in cells. The expression of and , two transsulfuration pathway genes encoding cystathionine gamma-lyase (CGL) and cystathionine beta-synthase (CBS), were also decreased under mTORC1-Sch9 inhibition. Overexpression of or in cells or WT cells treated with rapamycin rescued the deficiency of HS production. Finally, we also observed a reduction in HS production and lowering of both mRNA and protein levels of CGL and CBS in cultured human cells treated with rapamycin to reduce mTORC1 pathway activity. Thus, our findings reveal a probably conserved mechanism in which HS production by the transsulfuration pathway is regulated by mTORC1-Sch9 signaling.