Doxorubicin (DOX) is an effective
anthracycline chemotherapeutic anticancer drug with its life-threatening
cardiotoxicity severely limiting its clinical application. Mitochondrial damage-induced cardiomyocyte death is considered an essential cue for DOX
cardiotoxicity. FUN14 domain containing 1 (FUNDC1) is a mitochondrial membrane
protein participating in the regulation of mitochondrial integrity in multiple diseases although its role in DOX
cardiomyopathy remains elusive. Here, we examined whether PANoptosis, a novel type of programmed cell death closely associated with mitochondrial damage, was involved in DOX-induced
heart injury, and FUNDC1-mediated regulation of cardiomyocyte PANoptosis, if any. FUNDC1 was downregulated in heart tissues in patients with
dilated cardiomyopathy (DCM) and DOX-challenged mice. FUNDC1 deficiency aggravated DOX-induced cardiac
dysfunction, mitochondrial injury, and cardiomyocyte PANoptosis. Further examination revealed that FUNDC1 countered cytoplasmic release of
mitochondrial DNA (
mtDNA) and activation of PANoptosome through interaction with mitochondrial Tu translation
elongation factor (TUFM), a key factor in the translational expression and repair of
mitochondrial DNA, via its 96-133
amino acid domain. TUFM intervention reversed FUNDC1-elicited protection against DOX-induced
mtDNA cytosolic release and cardiomyocyte PANoptosis. Our findings shed light toward a beneficial role of FUNDC1 in DOX
cardiotoxicity and cardiomyocyte PANoptosis, thus offering therapeutic promises in DOX-induced
cardiotoxicity.