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

Abstract

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.

Characterization and Duodenal Transcriptome Analysis of Chinese Beef Cattle With Divergent Feed Efficiency Using RNA-Seq

“…Of those genes, three were closely associated with mitochondrial energy metabolism (NDUFS1, HADHB, and ALDOA) and were significantly upregulated in the LRFI group. NDUFS1 encodes one subunit of mitochondrial complex I, which is mainly involved in transferring electrons and maintaining the redox balance (Zou et al, 2021) in the first step of oxidative phosphorylation (Bertile et al, 2021). Knockdown of the NDUFS1 gene reduces membrane potential and mitochondrial mass in cardiomyocytes while also causing increased ROS production (Ni et al, 2019).…”

“…NADH is produced mainly through the electron respiratory chain to generate large amounts of ATP for life activities. The three identified DEGs-HADHB, ALDOA, and NDUFS1-are essential for fatty acid β-oxidation (Kao et al, 2006), glycolysis (Fu et al, 2018), and the function of the electron transport chain complex I, respectively (Zou et al, 2021). Moreover, other DEGs, such as CUL1 signigicantly down-regulated in the LRFI group (knockdown can lead to oxidative injury) (Goo et al, 2017), RFN4 signigicantly up-regulated in the LRFI group (deficiency of it can result in mitochondrial stress) (Syota et al, 2008), LDAH signigicantly down-regulated in the LRFI group (it plays a primarily lipogenic role (MoranKatz et al, 1998)), INPPL1 signigicantly down-regulated in LRFI group (it shows a capacity to impair insulin signaling (Ueno and Nakazato, 2016)), were also involved in substance or energy metabolism.…”

Huoxue Qianyang Qutan recipe attenuates Ang II‑induced cardiomyocyte hypertrophy by regulating reactive oxygen species production

“…Mitochondria are double-membrane organelles that support a variety of physiological activities, including energy production, cell death and oxidative metabolism (9). Mitochondrial dysfunction has been implicated in the occurrence and development of cardiomyocyte hypertrophy (28). Mitochondrial biogenesis is essential for sustaining mitochondrial function and is related to ROS production (29).…”

Mitochondria in Pathological Cardiac Hypertrophy Research and Therapy

“…A recent study found that Ndusf1 was downregulated in TAC mouse models. Further gain- and loss-of-function analysis revealed that Ndusf1 deficiency deteriorated cardiac hypertrophic response ( 44 ). In vitro mechanistic exploration showed that the mitochondrial DNA content in CMs was significantly decreased after Ndusf1 deletion, consistently, loss of Ndusf1 dramatically elevated ROS production in CMs.…”