Energy stress-mediated AMPK activation inhibits ferroptosis
By Hyemin Lee, Fereshteh Zandkarimi, Yilei Zhang, Jitendra Kumar Meena, Jongchan Kim, L. Zhuang, S. Tyagi, Li Ma, Thomas F. Westbrook, G. Steinberg and 3 more. Nature Cell Biology, 2020
985 citations recorded by the source corpus.
Energy stress depletes ATP and induces cell death. Here we identify an unexpected inhibitory role of energy stress on ferroptosis, a form of regulated cell death induced by iron-dependent lipid peroxidation. We found that ferroptotic cell death and lipid peroxidation can be inhibited by treatments that induce or mimic energy stress. Inactivation of AMP-activated protein kinase (AMPK), a sensor of cellular energy status, largely abolishes the protective effects of energy stress on ferroptosis in vitro and on ferroptosis-associated renal ischaemia–reperfusion injury in vivo. Cancer cells with high basal AMPK activation are resistant to ferroptosis and AMPK inactivation sensitizes these cells to ferroptosis. Functional and lipidomic analyses further link AMPK regulation of ferroptosis to AMPK-mediated phosphorylation of acetyl-CoA carboxylase and polyunsaturated fatty acid biosynthesis. Our study demonstrates that energy stress inhibits ferroptosis partly through AMPK and reveals an unexpected coupling between ferroptosis and AMPK-mediated energy-stress signalling. Lee et al. show that energy stress inhibits ferroptosis through AMPK activation and demonstrate a role for AMPK in ferroptosis-associated renal ischaemia–reperfusion injury in vivo.
Subfields: Cancer Research, Molecular Biology, Pulmonary and Respiratory Medicine
View Paper: https://www.semanticscholar.org/paper/0ddc270c653e4868945c05a0650fc309f71939bd
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Citations in the corpus
- Ferroptosis in cancer: from molecular mechanisms to therapeutic strategies (2024, background): “287,288 Lipid, amino acid, and vitamin metabolism also regulate ferroptosis sensitivity.”
- Ferroptosis: mechanisms and links with diseases (2021, background): “AMP-activated protein kinase (AMPK), a sensor of cellular energy status, can regulate ferroptosis via AMPK-mediated phosphorylation of acetyl-CoA carboxylase (ACC) and polyunsaturated fatty acid biosynthesis.(27) Liver kinase B1 (LKB1) is a main upstream kinase responsible for the activation of AMPK”
- Ferroptosis in infection, inflammation, and immunity (2021, background): “, 2021) or an energy sensor: adenosine monophosphate–activated protein kinase (AMPK; Lee et al., 2020; Li et al., 2020a; Song et al., 2021; Song et al., 2018; Zhao et al., 2020).”
- The cell biology of ferroptosis (2024, positive): “…and can phosphorylate and inhibit ACC1 and ACC2, which ultimately lowers ferroptosis sensitivity by reducing the abundance of oxidizable PUFA-containing membrane phospholipids (for example, PE 18:0/22:4) 30,182 , perhaps by limiting the malonyl-CoA-dependent elongation of shorter-chain PUFAs.”