AIFM2 blocks ferroptosis independent of ubiquinol metabolism

• Published in: Biochemical and biophysical research communications Vol. 523; no. 4; pp. 966 - 971
• Main Authors: Dai, Enyong, Zhang, Wenlong, Cong, Dan, Kang, Rui, Wang, Jing, Tang, Daolin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19.03.2020
• Subjects: AIFM2; Animals; antineoplastic activity; antioxidants; Antioxidants - metabolism; Apoptosis Regulatory Proteins - metabolism; Cell Line, Tumor; Cell Membrane - metabolism; coenzyme Q10; CoQ10; Endosomal Sorting Complexes Required for Transport - metabolism; ESCRT; Ferroptosis; Humans; Lipid peroxidation; metabolism; mice; Mice, Nude; Mitochondrial Proteins - metabolism; neoplasm cells; neoplasms; plasma membrane; Ubiquinol; Ubiquinone - analogs & derivatives; Ubiquinone - metabolism; xenotransplantation; NFE2L2/NRF2; ESCRT; GPX4; CoQ10; Lipid peroxidation; Ferroptosis; ACSL4; HMGB1; MDA; SLC7A11; Ubiquinol; AIFM2; GSH; CHMP5
• ISSN: 0006-291X; 1090-2104; 1090-2104
• DOI: 10.1016/j.bbrc.2020.01.066

Ferroptosis is a multi-step regulated cell death that is characterized by excessive iron accumulation and lipid peroxidation. Cancer cells can acquire resistance to ferroptosis by the upregulation of anti-ferroptotic proteins or by the downregulation of pro-ferroptotic proteins. Apoptosis-inducing factor mitochondria-associated 2 (AIFM2, also known as FSP1 or PRG3) has been recently demonstrated as an endogenous ferroptosis suppressor, but its mechanism remains obscure. Here, we show that AIFM2 blocks erastin-, sorafenib-, and RSL3-induced ferroptotic cancer cell death through a mechanism independent of ubiquinol, the reduced and active antioxidant form of coenzyme Q10. In contrast, AIFM2-dependent endosomal sorting complexes required for transport (ESCRT)-III recruitment in the plasma membrane is responsible for ferroptosis resistance through the activation of a membrane repair mechanism that regulates membrane budding and fission. Importantly, the genetic inhibition of the AIFM2-dependent ESCRT-III pathway increases the anticancer activity of sorafenib in a xenograft tumor mouse model. These findings shed new light on the mechanism involved in ferroptosis resistance during tumor therapy. •AIFM2 is a negative regulator of ferroptosis in vitro.•The ubiquinol-dependent antioxidant system is not essential for AIFM2-mediated ferroptosis resistance.•The ESCRT-III–dependent membrane repair is required for AIFM2-mediated ferroptosis resistance.•The AIFM2–ESCRT-III pathway promotes ferroptosis resistance in vivo.