Follicle stimulating hormone controls granulosa cell glutamine synthesis to regulate ovulation

Polycystic ovary syndrome(PCOS)is the leading cause of anovulatory infertility.Inadequate understanding of the ovulation drivers hinders PCOS intervention.Herein,we report that follicle stimulating hormone(FSH)controls follicular fluid(FF)glutamine levels to determine ovulation.Murine ovulation starts from FF-exposing granulosa cell(GC)apoptosis.FF glutamine,which decreases in pre-ovulation porcine FF,elevates in PCOS patients FF.High-glutamine chow to elevate FF glutamine inhibits mouse GC apoptosis and induces hormonal,metabolic,and morphologic PCOS traits.Mechanistically,follicle-development-driving FSH promotes GC glutamine synthesis to elevate FF glutamine,which maintain follicle wall integrity by inhibiting GC apoptosis through inactivating ASK1-JNK apoptotic pathway.FSH and glutamine inhibit the rapture of cultured murine follicles.Glutamine removal or ASK1-JNK pathway activation with metformin or AT-101 reversed PCOS traits in PCOS models that are induced with either glutamine or EsR1-KO.These suggest that glutamine,FSH,and ASK1-JNK pathway are targetable to alleviate PCOS.

Amino acids TORC(talk)to anabolism through uncharged tRNA

Anabolism is essential for proliferation as well as to replenish dysfunctional macromolecules in cells.Due to that both substantial building blocks and energy are required for anabolism,cells must double check whether these prerequisites are met before deciding to start anabolism.Amino acids are building blocks of protein synthesis,their sufficiency in cells is closely monitored by several mechanisms,which all are linked to protein synthesis.

Butyrate induces apoptosis by activating PDC and inhibiting complex I through SIRT3 inactivation

The underlying anticancer effects of butyrate,an end-product of the intestinal microbial fermentation of dietary fiber,remain elusive.Here,we report that butyrate promotes cancer cell apoptosis by acting as a SIRT3 inhibitor.Butyrate inhibits SIRT3 both in cultured cells and in vitro.Butyrate-induced PDHA1 hyperacetylation relieves the inhibitory phosphorylation of PDHA1 at serine 293,thereby activating an influx of glycolytic intermediates into the tricarboxylic acid(TCA)cycle and reversing the Warburg effect.Meanwhile,butyrate-induced hyperacetylation inactivates complex I of the electron transfer chain and prevents the utilization of TCA cycle intermediates.These metabolic stresses promote apoptosis in hyperglycolytic cancer cells,such as HCT116p53^(−/−)cells.SIRT3 deacetylates both PDHA1 and complex I.Genetic ablation of Sirt3 in mouse hepatocytes abrogated the ability of butyrate to induce apoptosis.Our results identify a butyrate-mediated anti-tumor mechanism and indicate that the combined activation of PDC and inhibition of complex I is a novel tumor treatment strategy.