Ndufs1 Deficiency Aggravates the Mitochondrial Membrane Potential Dysfunction in Pressure Overload-Induced Myocardial Hypertrophy

• Published in: Oxidative medicine and cellular longevity 2021, Vol.2021 (1), p.5545261-5545261
• Main Authors: Zou, Rongjun, Tao, Jun, Qiu, Junxiong, Shi, Wanting, Zou, Minghui, Chen, Weidan, Li, Wenlei, Zhou, Na, Wang, Shaoli, Ma, Li, Chen, Xinxin
• Format: Article
• Language: English
• Subjects: Angiotensin II; Animals; Atrial Natriuretic Factor - metabolism; Biomarkers - metabolism; Cardiac function; Cardiomegaly - metabolism; Cardiomegaly - pathology; Cardiomyocytes; Constriction, Pathologic; Datasets; Down-Regulation; Gene expression; Heart failure; Male; Membrane Potential, Mitochondrial; Mice; Mice, Inbred C57BL; Mitochondria, Heart - metabolism; Myocardium - metabolism; Myocardium - pathology; Myocytes, Cardiac - metabolism; Myosin Heavy Chains - metabolism; NADH Dehydrogenase - deficiency; NADH Dehydrogenase - metabolism; Natriuretic Peptide, Brain - metabolism; Pathophysiology; Phosphorylation; Pressure; Principal components analysis; Rats; Reactive oxygen species; RNA-Seq; Single-Cell Analysis
• ISSN: 1942-0900; 1942-0994
• DOI: 10.1155/2021/5545261

Mitochondrial dysfunction has been suggested to be the key factor in the development and progression of cardiac hypertrophy. The onset of mitochondrial dysfunction and the mechanisms underlying the development of cardiac hypertrophy (CH) are incompletely understood. The present study is based on the use of multiple bioinformatics analyses for the organization and analysis of scRNA-seq and microarray datasets from a transverse aortic constriction (TAC) model to examine the potential role of mitochondrial dysfunction in the pathophysiology of CH. The results showed that NADH:ubiquinone oxidoreductase core subunit S1- (Ndufs1-) dependent mitochondrial dysfunction plays a key role in pressure overload-induced CH. Furthermore, in vivo animal studies using a TAC mouse model of CH showed that Ndufs1 expression was significantly downregulated in hypertrophic heart tissue compared to that in normal controls. In an in vitro model of angiotensin II- (Ang II-) induced cardiomyocyte hypertrophy, Ang II treatment significantly downregulated the expression of Ndufs1 in cardiomyocytes. In vitro mechanistic studies showed that Ndufs1 knockdown induced CH; decreased the mitochondrial DNA content, mitochondrial membrane potential (MMP), and mitochondrial mass; and increased the production of mitochondrial reactive oxygen species (ROS) in cardiomyocytes. On the other hand, Ang II treatment upregulated the expression levels of atrial natriuretic peptide, brain natriuretic peptide, and myosin heavy chain beta; decreased the mitochondrial DNA content, MMP, and mitochondrial mass; and increased mitochondrial ROS production in cardiomyocytes. The Ang II-mediated effects were significantly attenuated by overexpression of Ndufs1 in rat cardiomyocytes. In conclusion, our results demonstrate downregulation of Ndufs1 in hypertrophic heart tissue, and the results of mechanistic studies suggest that Ndufs1 deficiency may cause mitochondrial dysfunction in cardiomyocytes, which may be associated with the development and progression of CH.