Mitochondrial aspartate/glutamate carrier AGC1 regulates cardiac function via Drp1-mediated mitochondrial fission in doxorubicin-induced cardiomyopathy

Yan Xia; Jiayu Jin; Ao Chen; Danbo Lu; Xinyu Che; Jiaqi Ma; Su Li; Ming Yin; Zheng Yang; Hao Lu; Chenguang Li; Jinxiang Chen; Muyin Liu; Yuan Wu; Hui Gong; Yunzeng Zou; Zhangwei Chen; Juying Qian; Junbo Ge

doi:10.1016/j.trsl.2023.06.004

Mitochondrial aspartate/glutamate carrier AGC1 regulates cardiac function via Drp1-mediated mitochondrial fission in doxorubicin-induced cardiomyopathy

Transl Res. 2023 Nov:261:28-40. doi: 10.1016/j.trsl.2023.06.004. Epub 2023 Jul 3.

Authors

Yan Xia¹, Jiayu Jin², Ao Chen¹, Danbo Lu¹, Xinyu Che¹, Jiaqi Ma¹, Su Li¹, Ming Yin¹, Zheng Yang¹, Hao Lu¹, Chenguang Li¹, Jinxiang Chen¹, Muyin Liu¹, Yuan Wu¹, Hui Gong¹, Yunzeng Zou¹, Zhangwei Chen³, Juying Qian⁴, Junbo Ge⁵

Affiliations

¹ Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai Clinical Research Center for Interventional Medicine, Shanghai 200032, China.
² Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Shanghai Key Laboratory of Bioactive Small Molecules, Fudan University, Shanghai 200032, China.
³ Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai Clinical Research Center for Interventional Medicine, Shanghai 200032, China. Electronic address: chen.zhangwei@zs-hospital.sh.cn.
⁴ Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai Clinical Research Center for Interventional Medicine, Shanghai 200032, China. Electronic address: qian.juying@zs-hospital.sh.cn.
⁵ Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai Clinical Research Center for Interventional Medicine, Shanghai 200032, China. Electronic address: ge.junbo@zs-hospital.sh.cn.

PMID: 37402419
DOI: 10.1016/j.trsl.2023.06.004

Abstract

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.

Keywords: AGC1; Dilated cardiomyopathy; Doxorubicin; Drp1; Mitochondrial fission.