Mitofusin 2 Participates in Mitophagy and Mitochondrial Fusion Against Angiotensin II-Induced Cardiomyocyte Injury

Wenjun Xiong; Zhuang Ma; Dongqi An; Zuheng Liu; Wanqiang Cai; Yujia Bai; Qiong Zhan; Wenyan Lai; Qingchun Zeng; Hao Ren; Dingli Xu

doi:10.3389/fphys.2019.00411

Mitofusin 2 Participates in Mitophagy and Mitochondrial Fusion Against Angiotensin II-Induced Cardiomyocyte Injury

Front Physiol. 2019 Apr 10:10:411. doi: 10.3389/fphys.2019.00411. eCollection 2019.

Authors

Wenjun Xiong^{1

2}, Zhuang Ma^{1

2}, Dongqi An^{1

2}, Zuheng Liu^{1

2}, Wanqiang Cai^{1

2}, Yujia Bai^{1

2}, Qiong Zhan^{1

2}, Wenyan Lai^{1

2}, Qingchun Zeng^{1

2}, Hao Ren^{2

3}, Dingli Xu^{1

2}

Affiliations

¹ State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
² Key Laboratory for Organ Failure Research, Ministry of Education of the People's Republic of China, Guangzhou, China.
³ Department of Rheumatology, Nanfang Hospital, Southern Medical University, Guangzhou, China.

Abstract

Background: Mitochondrial dynamics play a critical role in mitochondrial function. The mitofusin 2 (MFN2) gene encodes a mitochondrial membrane protein that participates in mitochondrial fusion to maintain and operate the mitochondrial network. Moreover, MFN2 is essential for mitophagy. In Ang II-induced cardiac remodeling, the combined effects of MFN2-mediated mitochondrial fusion and mitophagy are unclear. This study was designed to explore a novel strategy for preventing cardiomyocyte injury via modulation of mitochondrial dynamics.

Methods: We studied the function of MFN2 in mitochondrial fusion and mitophagy in Ang II-stimulated cardiomyocyte injury. Cardiomyocyte injury experiments, including reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP), and apoptosis rate of cardiomyocytes were performed. The mitochondrial morphology in cardiomyocytes was examined via transmission electron microscopy (TEM) and confocal microscopy. Autophagic levels in response to Ang II were examined by immunoblotting of autophagy-related proteins. Moreover, PINK1/MFN2/Parkin pathway-related proteins were examined.

Results: With stimulation by Ang II, MFN2 expression was progressively reduced. MFN2 deficiency impaired mitochondrial quality, resulting in exacerbated mitochondrial damage induced by Ang II. The Ang II-induced increases in ROS production and apoptosis rate were alleviated by MFN2 overexpression. Moreover, MFN2 alleviated the Ang II-induced reduction in MMP. MFN2 promoted mitochondrial fusion, and MFN2 promoted Parkin translocation and phosphorylation, leading to mitochondrial autophagy. The effects of MFN2 overexpression were reversed by autophagy inhibitors.

Conclusion: Mitofusin 2 promotes Parkin translocation and phosphorylation, leading to mitophagy to clear damaged mitochondria. However, the beneficial effects of MFN2 were reversed by autophagy inhibitors. Additionally, MFN2 participates in mitochondrial fusion to maintain mitochondrial quality. Thus, MFN2 participated in mitophagy and mitochondrial fusion against Ang II-induced cardiomyocyte injury.

Keywords: MFN2; ROS; angiotensin II; autophagy; mitochondria.