Abstract
BackgroundMitochondrial 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.MethodsWe 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.ResultsWith 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.ConclusionMitofusin 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.
Highlights
Ventricular remodeling is the core foundation for the development of heart failure (Hill and Olson, 2008)
We found that mitofusin 2 (MFN2) maintained mitochondrial quality through participating in mitophagy and mitochondrial fusion in an Ang angiotensin II (II)-induced cardiomyocyte injury model
Cardiomyocytes were divided into two groups: (1) Control, cells were not treated with Ang II, and (2) Ang II, cells were treated with 1 μM
Summary
Ventricular remodeling is the core foundation for the development of heart failure (Hill and Olson, 2008). Pathological remodeling is typically due to a number of causes that result in increased pressure or volume, causing pressure or volume overload in the heart (Burchfield et al, 2013). This pathological process may include ventricular hypertrophy, ventricular dilation, cardiomegaly, and other changes. Ang II can activate a number of signaling pathways to induce cardiac inflammation, hypertrophy, and fibrosis, leading to ventricular remodeling (Mehta and Griendling, 2007; Trachtenberg and Hare, 2017). 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
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