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

Significance

Mitochondria play a vital role in the progression of ferroptosis, an iron-dependent programmed necrosis that is associated with a series of diseases, including cardiomyopathy and heart ischemia–reperfusion injury. However, the molecular mechanism underpinning the link between mitochondria and ferroptosis remains incompletely understood. Here, we found that mitochondrial outer membrane protein FUN14 domain–containing 2, also known as HCBP6 (FUNDC2), could interact with and destabilize SLC25A11 to affect mitochondrial glutathione (mitoGSH) levels, and thus to regulate ferroptosis. This FUNDC2–SLC25A11 axis serves as a pathway for the regulation of ferroptosis through mitochondria and provides insights into the therapeutic interventions of ferroptosis-related diseases.

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.