2. Academic Validation
  3. Mitochondrial outer membrane protein FUNDC2 promotes ferroptosis and contributes to doxorubicin-induced cardiomyopathy

Mitochondrial outer membrane protein FUNDC2 promotes ferroptosis and contributes to doxorubicin-induced cardiomyopathy

  • Proc Natl Acad Sci U S A. 2022 Sep 6;119(36):e2117396119. doi: 10.1073/pnas.2117396119.
Na Ta 1 2 3,  Chuanren Qu 1 2 3,  Hao Wu 4,  Di Zhang 1 5,  Tiantian Sun 5,  Yanjun Li 5,  Jun Wang 1 3,  Xiaohui Wang 1 3,  Tieshan Tang 1 2 3,  Quan Chen 5,  Lei Liu 1 2 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
  • 2 University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 3 Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
  • 4 State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China.
  • 5 Interdisciplinary Center of Cell Response, State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China.
PMID: 36037337 DOI: 10.1073/pnas.2117396119
Abstract

Ferroptosis is an iron-dependent programmed necrosis characterized by glutathione (GSH) depletion and lipid peroxidation (LPO). Armed with both the pro- and antiferroptosis machineries, mitochondria play a central role in Ferroptosis. However, how mitochondria sense the stress to activate Ferroptosis under (patho-)physiological settings remains incompletely understood. Here, we show that FUN14 domain-containing 2, also known as HCBP6 (FUNDC2), a highly conserved and ubiquitously expressed mitochondrial outer membrane protein, regulates Ferroptosis and contributes to doxorubicin (DOX)-induced cardiomyopathy. We showed that knockout of FUNDC2 protected mice from DOX-induced cardiac injury by preventing Ferroptosis. Mechanistic studies reveal that FUNDC2 interacts with SLC25A11, the mitochondrial glutathione transporter, to regulate mitoGSH levels. Specifically, knockdown of SLC25A11 in FUNDC2-knockout (KO) cells reduced mitoGSH and augmented erasin-induced Ferroptosis. FUNDC2 also affected the stability of both SLC25A11 and Glutathione Peroxidase 4 (GPX4), key regulators for Ferroptosis. Our results demonstrate that FUNDC2 modulates ferroptotic stress via regulating mitoGSH and further support a therapeutic strategy of cardioprotection by preventing mitoGSH depletion and Ferroptosis.

Keywords

FUNDC2; SLC25A11; ferroptosis; mitoGSH; mitochondria.

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