SIRT7 upregulation protects against TKI-induced cardiotoxicity by inhibiting MCU-mediated mitochondrial calcium overload.

BACKGROUND

Tyrosine kinase inhibitors (TKIs) are potent anticancer agents; however, their clinical application is often restricted because of cardiotoxic effects. The mechanisms underlying cardiotoxicity that are shared across different TKIs remain inadequately understood.

PURPOSE: This study aimed to investigate the role of sirtuin 7 (SIRT7) in regulating mitochondrial calcium homeostasis during TKI-induced cardiomyocyte injury and determine whether the SIRT7-mitochondrial calcium uniporter (MCU) axis could serve as a common protective target.

METHODS

AC16 cells were treated for 72 h with three TKIs: sunitinib (4.11 µM, IC30), trametinib (12.21 µM, IC30), and imatinib (21.84 µM, IC30). Cell viability, cardiomyocyte injury markers (N-terminal pro-brain natriuretic peptide and cardiac troponin I), cytosolic and mitochondrial Ca2+ levels, mitochondrial membrane potential, adenosine triphosphate (ATP) content, and endoplasmic reticulum-mitochondria contacts assessed using transmission electron microscopy were evaluated. Proteomic analysis was performed to identify differentially expressed proteins shared across treatments. In human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), contraction amplitude was measured using an impedance-based system, and mitochondrial Ca2+ overload was evaluated.

RESULTS

All three TKIs induced concentration-dependent injury in AC16 cells, accompanied by mitochondrial Ca2+ overload, ATP depletion exceeding 50%, and increased mitochondria-endoplasmic reticulum (ER) contacts. Proteomic analysis identified consistent SIRT7 downregulation across the three TKI treatments. SIRT7 overexpression mitigated TKI-induced cellular damage, reversed MCU upregulation and functional activation, restored mitochondrial function, and reduced excessive mitochondria-ER contacts. In hiPSC-CMs, SIRT7 overexpression reduced mitochondrial Ca2+ overload and prevented TKI-induced contraction inhibition.

CONCLUSION

SIRT7 upregulation protects against TKI-induced cardiotoxicity by inhibiting MCU-mediated mitochondrial calcium overload.