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MESH1 is a cytosolic NADPH phosphatase that regulates ferroptosis.

Publication ,  Journal Article
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 ...
Published in: Nat Metab
March 2020

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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Published In

Nat Metab

DOI

EISSN

2522-5812

Publication Date

March 2020

Volume

2

Issue

3

Start / End Page

270 / 277

Location

Germany

Related Subject Headings

  • Pyrophosphatases
  • NADP
  • Humans
  • Ferroptosis
  • Cytosol
  • 3210 Nutrition and dietetics
  • 3208 Medical physiology
  • 3205 Medical biochemistry and metabolomics
 

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Ding, C.-K., Rose, J., Sun, T., Wu, J., Chen, P.-H., Lin, C.-C., … Chi, J.-T. (2020). MESH1 is a cytosolic NADPH phosphatase that regulates ferroptosis. Nat Metab, 2(3), 270–277. https://doi.org/10.1038/s42255-020-0181-1
Ding, Chien-Kuang Cornelia, Joshua Rose, Tianai Sun, Jianli Wu, Po-Han Chen, Chao-Chieh Lin, Wen-Hsuan Yang, et al. “MESH1 is a cytosolic NADPH phosphatase that regulates ferroptosis.Nat Metab 2, no. 3 (March 2020): 270–77. https://doi.org/10.1038/s42255-020-0181-1.
Ding C-KC, Rose J, Sun T, Wu J, Chen P-H, Lin C-C, et al. MESH1 is a cytosolic NADPH phosphatase that regulates ferroptosis. Nat Metab. 2020 Mar;2(3):270–7.
Ding, Chien-Kuang Cornelia, et al. “MESH1 is a cytosolic NADPH phosphatase that regulates ferroptosis.Nat Metab, vol. 2, no. 3, Mar. 2020, pp. 270–77. Pubmed, doi:10.1038/s42255-020-0181-1.
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. MESH1 is a cytosolic NADPH phosphatase that regulates ferroptosis. Nat Metab. 2020 Mar;2(3):270–277.

Published In

Nat Metab

DOI

EISSN

2522-5812

Publication Date

March 2020

Volume

2

Issue

3

Start / End Page

270 / 277

Location

Germany

Related Subject Headings

  • Pyrophosphatases
  • NADP
  • Humans
  • Ferroptosis
  • Cytosol
  • 3210 Nutrition and dietetics
  • 3208 Medical physiology
  • 3205 Medical biochemistry and metabolomics