Cardiac-specific deletion of voltage dependent anion channel 2 leads to dilated cardiomyopathy by altering calcium homeostasis

Voltage dependent anion channel 2 (VDAC2) is an outer mitochondrial membrane porin known to play a significant role in apoptosis and calcium signaling. Abnormalities in calcium homeostasis often leads to electrical and contractile dysfunction and can cause dilated cardiomyopathy and heart failure. However, the specific role of VDAC2 in intracellular calcium dynamics and cardiac function is not well understood. To elucidate the role of VDAC2 in calcium homeostasis, we generated a cardiac ventricular myocyte-specific developmental deletion of Vdac2 in mice. Our results indicate that loss of VDAC2 in the myocardium causes severe impairment in excitation-contraction coupling by altering both intracellular and mitochondrial calcium signaling. We also observed adverse cardiac remodeling which progressed to severe cardiomyopathy and death. Reintroduction of VDAC2 in 6-week-old knock-out mice partially rescued the cardiomyopathy phenotype. Activation of VDAC2 by efsevin increased cardiac contractile force in a mouse model of pressure-overload induced heart failure. In conclusion, our findings demonstrate that VDAC2 plays a crucial role in cardiac function by influencing cellular calcium signaling. Through this novel role in cellular calcium dynamics and excitation-contraction coupling VDAC2 emerges as a plausible therapeutic target for heart failure. 16-week old VDAC2 KO vs VDAC2 WT Cardiac tissue电压依赖性阴离子通道2（Voltage dependent anion channel 2, VDAC2）是一类线粒体外膜孔蛋白，已被证实于细胞凋亡及钙信号通路中发挥关键作用。钙稳态异常常引发心脏电活动与收缩功能障碍，进而可导致扩张型心肌病与心力衰竭。然而，VDAC2在细胞内钙动力学及心脏功能中的具体调控机制尚未完全明确。为阐明VDAC2在钙稳态中的作用，我们构建了小鼠心脏心室肌细胞特异性发育性敲除Vdac2的模型。研究结果显示，心肌组织中VDAC2的缺失会通过改变细胞内及线粒体钙信号通路，严重损伤兴奋-收缩耦联过程。此外，我们还观察到不良心脏重构逐渐进展为重度心肌病并最终导致死亡。向6周龄的VDAC2敲除小鼠中重新导入VDAC2，可部分逆转心肌病表型。使用efsevin激活VDAC2，可在压力负荷诱导的心力衰竭小鼠模型中显著增强心脏收缩力。综上，本研究结果表明，VDAC2通过调控细胞钙信号通路在心脏功能中扮演关键角色。凭借其在细胞内钙动力学及兴奋-收缩耦联中的全新功能，VDAC2有望成为心力衰竭的潜在治疗靶点。16周龄VDAC2敲除（KO）小鼠与野生型（WT）心脏组织