MESH1 is a cytosolic NADPH phosphatase that regulates ferroptosis.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Ding, C-KC; Rose, J; Sun, T; Wu, J; Chen, P-H; Lin, C-C; Yang, W-H; Chen, K-Y; Lee, H; Xu, E; Tian, S; Akinwuntan, J; Zhao, J; Guan, Z; Zhou, P; Chi, J-T

Published Date

  • March 2020

Published In

Volume / Issue

  • 2 / 3

Start / End Page

  • 270 - 277

PubMed ID

  • 32462112

Pubmed Central ID

  • PMC7252213

Electronic International Standard Serial Number (EISSN)

  • 2522-5812

International Standard Serial Number (ISSN)

  • 2522-5812

Digital Object Identifier (DOI)

  • 10.1038/s42255-020-0181-1


  • eng