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Updated: Dec 20, 2025
Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
MESH1 is a cytosolic NADPH phosphatase that regulates ferroptosis
Chien-Kuang Cornelia Ding1,2, Joshua Rose3, Tianai Sun1,2
1Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, USA.
Abstract:
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.
Insights
Human MESH1 is a cytosolic NADPH phosphatase that promotes ferroptosis, a form of programmed cell death. Depleting MESH1 sustains NADPH levels, protecting cells from ferroptosis and highlighting NADPH regulation in cell survival.
Area of Science:
- Cell Biology
- Biochemistry
- Molecular Biology
Background:
- The bacterial stringent response involves (p)ppGpp metabolism by RelA and SpoT homologues for stress survival.
- Mammalian cells possess MESH1, a homologue of the bacterial (p)ppGpp hydrolase SpoT, but lack identified (p)ppGpp pathways.
- Ferroptosis is a regulated form of cell death influenced by cellular metabolism.
Purpose of the Study:
- To investigate the function of human MESH1 in mammalian cells.
- To determine the role of MESH1 in ferroptosis.
- To elucidate the relationship between MESH1, NADPH, and ferroptosis.
Main Methods:
- Crystal structure visualization of MESH1-NADPH complex.
- Overexpression and depletion of MESH1 in mammalian cells.
- Measurement of NADPH, GSH, and lipid peroxidation levels.
- Assessment of ferroptosis sensitivity under various conditions.
- Genetic manipulation of NADK and NADK2.
Main Results:
- Human MESH1 functions as an efficient cytosolic NADPH phosphatase.
- MESH1 overexpression depletes NADPH, sensitizing cells to ferroptosis.
- MESH1 depletion sustains NADPH and GSH, enhances ferroptosis survival, and reduces lipid peroxidation.
- Ferroptotic protection by MESH1 depletion depends on cytosolic NADK, not mitochondrial NADK2.
Conclusions:
- Human MESH1 regulates ferroptosis through its NADPH phosphatase activity.
- Cytosolic NADPH levels are critical for ferroptosis regulation in mammalian cells.
- MESH1 represents a novel target for modulating ferroptosis and cellular redox homeostasis.
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