Energy-stress-mediated AMPK activation inhibits ferroptosis

Abstract

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 ischemia/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 (ACC) and polyunsaturated fatty acid biosynthesis. Together, our study demonstrates that energy stress inhibits ferroptosis partly through AMPK, and reveals an unexpected coupling between ferroptosis and AMPK-mediated energy stress signaling.

Oxidative Damage and Antioxidant Defense in Ferroptosis

“…AMPK-mediated BECN1 (a key autophagy regulator) phosphorylation promotes ferroptosis through the inhibition of system xc − activity (Song et al, 2018). In contrast, AMPK-mediated acetyl-CoA carboxylase alpha (ACACA) phosphorylation blocks ferroptosis through the inhibition of fatty acid biosynthesis (Lee et al, 2020). Additional signals, currently unknown, are needed to explain the substrate selectivity of AMPK-related ferroptosis regulation.…”

Ferroptosis in Cancer Treatment: Another Way to Rome

“…However, a recent study proposed the contradictory conclusion that cancer cells with high basal AMPK activation are resistant to ferroptosis and AMPK inactivation sensitizes these cells to ferroptosis. Functional and lipidomic analyses have further revealed that ferroptosis is regulated via AMPK-mediated phosphorylation of acetyl-CoA carboxylase and restrained biosynthesis of PUFAs or other fatty acids (135). It is possible that the function of AMPK in regulating ferroptosis is context dependent, which awaits further exploration in future studies.…”

LKB1-AMPK axis negatively regulates ferroptosis by inhibiting fatty acid synthesis

“…While we are preparing this manuscript, Lee et al also reported that AMPK negatively regulates ferroptosis by inhibiting fatty acid synthesis. 5 As LKB1 is frequently mutated in cancer, this study has clear implications for cancer therapies. Our finding suggests that there might be a dose-responsive window for cancers that contain certain genetic signatures and that ferroptosis-inducing cancer therapies might have considerable benefits in overcoming cancer resistance to current treatments.…”