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Merck

MESH1 is a cytosolic NADPH phosphatase that regulates ferroptosis.

Nature metabolism (2020-05-29)
Chien-Kuang Cornelia Ding, Joshua Rose, Tianai Sun, Jianli Wu, Po-Han Chen, Chao-Chieh Lin, Wen-Hsuan Yang, Kai-Yuan Chen, Hana Lee, Emily Xu, Sarah Tian, Jadesola Akinwuntan, Jinshi Zhao, Ziqiang Guan, Pei Zhou, Jen-Tsan Chi
RESUMEN

Critical to the bacterial stringent response is the rapid relocation of resources from proliferation toward stress survival through the respective accumulation and degradation of (p)ppGpp by RelA and SpoT homologues. While mammalian genomes encode MESH1, a homologue of the bacterial (p)ppGpp hydrolase SpoT, neither (p)ppGpp nor its synthetase has been identified in mammalian cells. Here, we show that human MESH1 is an efficient cytosolic NADPH phosphatase that facilitates ferroptosis. Visualization of the MESH1-NADPH crystal structure revealed a bona fide affinity for the NADPH substrate. Ferroptosis-inducing erastin or cystine deprivation elevates MESH1, whose overexpression depletes NADPH and sensitizes cells to ferroptosis, whereas MESH1 depletion promotes ferroptosis survival by sustaining the levels of NADPH and GSH and by reducing lipid peroxidation. The ferroptotic protection by MESH1 depletion is ablated by suppression of the cytosolic NAD(H) kinase, NADK, but not its mitochondrial counterpart NADK2. Collectively, these data shed light on the importance of cytosolic NADPH levels and their regulation under ferroptosis-inducing conditions in mammalian cells.

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Roche
cOmplete, Mini, conjunto de inhibidores de proteasas sin EDTA, Protease Inhibitor Cocktail Tablets provided in a glass vial, Tablets provided in a glass vial
Sigma-Aldrich
Tampón RIPA
Sigma-Aldrich
L-Metionina, from non-animal source, meets EP, JP, USP testing specifications, suitable for cell culture, 99.0-101.0%
Sigma-Aldrich
L-Cistina dihydrochloride, from non-animal source, BioReagent, suitable for cell culture, ≥98.0% dry basis
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Suero fetal bovino, USA origin, Dialyzed by ultrafiltration against 0.15 M NaCl, sterile-filtered, suitable for cell culture