Energy Stress Inhibits Ferroptotic Cell Death via AMPK Activation

Dysregulation of ferroptosis, a form of programmed cell death in which cells accumulate lipid peroxides in an iron-dependent fashion, has been linked to cancer and other pathologies. Despite the fact that glucose starvation is associated with increases in levels of reactive oxygen species, which could generate lipid peroxides, Lee, Zandkarimi, and colleagues unexpectedly found that energy stress protected cells against ferroptosis. The mechanism of ferroptosis inhibition appeared to be dependent on AMP-activated protein kinase (AMPK), and, correspondingly, further investigation revealed that inactivation of AMPK in a normally ferroptosis-resistant cancer cell line rendered cells sensitive to ferroptosis. Mechanistically, additional experiments suggested this ferroptosis inhibition was dependent on phosphorylation of acetyl-CoA carboxylase 1 and 2 (ACC1/2) by AMPK, which prevents ACC1/2-mediated promotion of fatty-acid synthesis and inhibition of fatty-acid oxidation. Activation of AMPK was also associated with reduced levels of polyunsaturated fatty acid–containing lipids, which may also contribute to the modulation of ferroptosis sensitivity by AMPK. In a mouse model of renal ischemia–reperfusion injury (IRI), which has been associated with ferroptosis in previous studies, treatment with an inhibitor of ferroptosis reduced the pathologic effects of renal IRI, as did AMPK activation triggered by energy stress. Collectively, these results establish AMPK as a key regulator of ferroptosis in vitro and in vivo. Interestingly, the function of AMPK in cancer appears to vary depending on several factors; for example, AMPK can act as a tumor suppressor by blocking biosynthesis of proteins or fatty acids, but it can also enhance tumor growth by preventing cell death during energy stress, and AMPK overexpression or amplification has been observed in some cancers. Whether AMPK-mediated ferroptosis inhibition contributes to its tumor-promoting effects in some circumstances would be an intriguing topic for further research.

Lee H, Zandkarimi F, Zhang Y, Meena JK, Kim J, Zhuang L, et al. Energy-stress-mediated AMPK activation inhibits ferroptosis. Nat Cell Biol 2020;22:225–34.

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