Mitochondrial aspartate/glutamate carrier AGC1 regulates cardiac function via Drp1-mediated mitochondrial fission in doxorubicin-induced cardiomyopathy
Mitochondrial aspartate/glutamate carrier AGC1 regulates cardiac function via Drp1-mediated mitochondrial fission in doxorubicin-induced cardiomyopathy
复制标题
DOI：
10.1016/j.trsl.2023.06.004
复制
发表时间：
2023-09-25
影响因子：
7.8
通讯作者：
Ge，Junbo
中科院分区：
文献类型：
--
作者：
Xia，Yan;Jin，Jiayu;Ge，Junbo
线粒体分裂在扩张型心肌病（DCM）的发病机制中已被注意到，但其潜在的特定调节机制，特别是在阿霉素（DOX）诱导的心肌病的发展中仍不清楚。在本研究中，我们探讨了天冬氨酸-谷氨酸载体1 （AGC1）是否与裂变蛋白动力蛋白相关蛋白1 （Drp1）相互作用，并揭示了dox诱导心肌病的功能和分子机制。基于DCM患者心脏组织的共免疫沉淀质谱（CO-IP MS）分析结果显示，AGC1表达在DCM诱导的损伤中显著上调，且AGC1水平与线粒体形态发生和功能密切相关。我们发现AGC1敲低通过阻止线粒体分裂保护小鼠免受dox诱导的心肌病，而AGC1在小鼠心脏中的过度表达导致心功能受损。从机制上讲，AGC1过表达可以上调Drp1的表达，并导致随后的线粒体过度分裂。具体而言，AGC1敲低或使用drp1特异性抑制剂Mdivi-1可减轻心肌细胞凋亡，抑制DOX暴露诱导的线粒体功能损伤。综上所述，我们的数据表明，AGC1作为DCM的新参与者，通过drp1介导的线粒体裂变调节心功能，这表明靶向AGC1- drp1轴可能是dox诱导的心肌病的潜在治疗策略。
Mitochondrial fission has been noted in the pathogenesis of dilated cardiomyopathy (DCM), but the underlying specific regulatory mechanism, especially in the development of doxorubicin (DOX)-induced cardiomyopathy remains unclear. In the present study, we explore whether the aspartate-glutamate carrier1 (AGC1) interacts with the fission protein dynamin-related protein 1 (Drp1) and reveal the functional and molecular mechanisms contributing to DOX-induced cardiomyopathy. Results of co-immunoprecipitation mass spectrometry (CO-IP MS) analysis based on heart tissue of DCM patients revealed that AGC1 expression was significantly upregulated in DCM-induced injury and AGC1 level was closely correlated with mitochondrial morphogenesis and function. We showed that AGC1 knockdown protected mice from DOX-induced cardiomyopathy by preventing mitochondrial fission, while the overexpression of AGC1 in the mouse heart led to impairment of cardiac function. Mechanistically, AGC1 overexpression could upregulate Drp1 expression and contribute to subsequent excessive mitochondrial fission. Specifically, AGC1 knockdown or the use of Drp1-specific inhibitor Mdivi-1 alleviated cardiomyocyte apoptosis and inhibited impairment of mitochondrial function induced by DOX exposure. In summary, our data illustrate that AGC1, as a novel contributor to DCM, regulates cardiac function via Drp1-mediated mitochondrial fission, indicating that targeting AGC1-Drp1 axis could be a potential therapeutic strategy for DOX-induced cardiomyopathy.