AIFM2 blocks ferroptosis independent of ubiquinol metabolism

Enyong Dai, Wenlong Zhang, Dan Cong, Rui Kang, Jing Wang, Daolin Tang

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)966-971
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume523
Issue number4
DOIs
StatePublished - Mar 19 2020

Keywords

  • AIFM2
  • CoQ10
  • ESCRT
  • Ferroptosis
  • Lipid peroxidation
  • Ubiquinol

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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