FUNDC1 Protects against Doxorubicin-Induced Cardiomyocyte PANoptosis through Stabilizing mtDNA via Interaction with TUMF

Abstract Doxorubicin (DOX) is an effective anti-cancer anthracyclines chemotherapy drug with its potentially 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 whether FUNDC1 regulated cardiomyocyte PANoptosis. 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 against 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. These findings shed light towards the protective role of FUNDC1 against DOX cardiotoxicity and cardiomyocyte PANoptosis, which provides a potentially therapeutic approach for Dox induced cardiotoxicity.