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