TY - JOUR
T1 - Energy-stress-mediated AMPK activation inhibits ferroptosis
AU - Lee, Hyemin
AU - Zandkarimi, Fereshteh
AU - Zhang, Yilei
AU - Meena, Jitendra Kumar
AU - Kim, Jongchan
AU - Zhuang, Li
AU - Tyagi, Siddhartha
AU - Ma, Li
AU - Westbrook, Thomas F.
AU - Steinberg, Gregory R.
AU - Nakada, Daisuke
AU - Stockwell, Brent R.
AU - Gan, Boyi
N1 - Funding Information:
We thank L. Brown for providing access to the instrumentation for the lipidomics experiments. This research was supported by the Andrew Sabin Family Fellow Award and the Bridge Fund from The University of Texas MD Anderson Cancer Center (to B.G.) and grants from the National Institutes of Health (grant no. R01CA181196 to B.G.; grant nos. R35CA209896, 1R61NS109407 and P01CA087497 to B.R.S.; grant nos. R01CA166051 and R01CA181029 to L.M.). J.K.M. is supported by the Susan G. Komen PDF Basic/Translational and Clinical Funding Program (grant no. PDF17487931). T.F.W. is supported in part by the DOD (grant no. 1W81XWH-18–1–0573), the National Institutes of Health and NCI (grant no. 1R01CA215226), The Welch Foundation (grant no. Q-0007) and the McNair Medical Institute. G.R.S. is supported by a Canada Research Chair and the J. Bruce Duncan Chair in Metabolic Diseases and research grants from the Canadian Institutes of Health Research (grant no. 201709FDN-CEBA-116200) and Diabetes Canada (grant no. DI-5-17-5302-GS). B.G. is an Andrew Sabin Family Fellow. This research was also supported by the National Institutes of Health Cancer Center Support Grant P30CA016672 to The University of Texas MD Anderson Cancer Center.
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2020/2/1
Y1 - 2020/2/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41556-020-0461-8
DO - 10.1038/s41556-020-0461-8
M3 - Article
C2 - 32029897
AN - SCOPUS:85079065261
SN - 1465-7392
VL - 22
SP - 225
EP - 234
JO - Nature cell biology
JF - Nature cell biology
IS - 2
ER -