MESH1 is a cytosolic NADPH phosphatase that regulates ferroptosis
Repository Usage Stats
© 2020, The Author(s), under exclusive licence to Springer Nature Limited. 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.
Published Version (Please cite this version)10.1038/s42255-020-0181-1
Publication InfoDing, Chien-Kuang Cornelia; Rose, Joshua; Sun, Tianai; Wu, Jianli; Chen, Po-Han; Lin, Chao-Chieh; ... Chi, Jen-Tsan (2020). MESH1 is a cytosolic NADPH phosphatase that regulates ferroptosis. Nature Metabolism, 2(3). pp. 270-277. 10.1038/s42255-020-0181-1. Retrieved from https://hdl.handle.net/10161/20284.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
More InfoShow full item record
Jen-Tsan Ashley Chi
Professor in Molecular Genetics and Mirobiology
We are using functional genomic approaches to investigate the nutrient signaling and stress adaptations of cancer cells when exposed to various nutrient deprivations and microenvironmental stress conditions. Recently, we focus on two areas. First, we are elucidating the genetic determinants and disease relevance of ferroptosis, a newly recognized form of cell death. Second, we have identified the mammalian stringent response pathway which is highly similar to bacterial stringent response, but
Research Professor in Biochemistry
We develop and apply mass spectrometry techniques to address biochemical and biomedical questions that are lipid-related. Research projects include: 1) Structural lipidomics o Develop and apply high resolution tandem mass spectrometry-based lipidomics for the discovery, structural elucidation and functional study of novel lipids. 2) Elucidation of novel pathways/enzymes of lipid biosynthesis and metabolism o Genetic, biochemical and MS a
Professor of Biochemistry
Protein-protein interactions play a pivotal role in the regulation of various cellular processes. The formation of higher order protein complexes is frequently accompanied by extensive structural remodeling of the individual components, varying from domain re-orientation to induced folding of unstructured elements. Nuclear Magnetic Resonance (NMR) spectroscopy is a powerful tool for macromolecular structure determination in solution. It has the unique advantage of being capable of elucidati
Alphabetical list of authors with Scholars@Duke profiles.
Articles written by Duke faculty are made available through the campus open access policy. For more information see: Duke Open Access Policy
Rights for Collection: Scholarly Articles
Works are deposited here by their authors, and represent their research and opinions, not that of Duke University. Some materials and descriptions may include offensive content. More info