Abstract
Mitochondrial dysfunction contributes to cardiovascular disorders, especially post-infarction cardiac injury, through incompletely characterized mechanisms. Among the latter, increasing evidence points to alterations in mitochondrial quality control, a range of adaptive responses regulating mitochondrial morphology and function. Optic atrophy 1 (Opa1) is a mitochondrial inner membrane GTPase known to promote mitochondrial fusion. In this study, hypoxia-mediated cardiomyocyte damage was induced to mimic post-infarction cardiac injury in vitro. Loss- and gain-of-function assays were then performed to evaluate the impact of Opa1 expression on mitochondrial quality control and cardiomyocyte survival and function. Hypoxic stress reduced cardiomyocyte viability, impaired contractile/relaxation functions, and augmented the synthesis of pro-inflammatory mediators. These effects were exacerbated by Opa1 knockdown, and significantly attenuated by Opa1 overexpression. Mitochondrial quality control was disturbed by hypoxia, as reflected by multiple mitochondrial deficits; i.e., increased fission, defective fusion, impaired mitophagy, decreased biogenesis, increased oxidative stress, and blunted respiration. By contrast, overexpression of Opa1 normalized mitochondrial quality control and sustained cardiomyocyte function. We also found that ERK, AMPK, and YAP signaling can regulate Opa1 expression. These results identify Opa1 as a novel regulator of mitochondrial quality control and highlight a key role for Opa1 in protecting cardiomyocytes against post-infarction cardiac injury.
Highlights
Acute myocardial infarction (AMI) is a common complication of ischemic cardiomyopathy, a major cause of morbidity and mortality worldwide (Davidson et al, 2018; Heusch, 2018)
To assess the role of Optic atrophy 1 (Opa1) in post-infarction cardiac damage, an in vitro model was established by introducing Opa1-expressing adenoviral vectors (Ad-Opa1) or a siRNA targeting Opa1 into primary cardiomyocytes isolated from neonatal mice
Compared to the control group, hypoxia stress significantly upregulated troponin T (TnT), troponin I (TnI), and creative kinase MB (CK-MB) levels. The upregulation of these three proteins was prevented by Ad-Opa1 transduction, whereas si-Opa1 transfection further augmented TnT, TnI, and CK-MB secretion
Summary
Acute myocardial infarction (AMI) is a common complication of ischemic cardiomyopathy, a major cause of morbidity and mortality worldwide (Davidson et al, 2018; Heusch, 2018). The damaged myocardium activates several mechanisms to sustain cardiac function, including an inflammatory response to remove injured cells, stimulation of fibroblast to repair infarcted tissue, augmentation of angiogenesis to enhance blood supply, and activation of neurohumoral mechanisms to maintain cardiac output (Zhou et al, 2018b; Harhous et al, 2019; Song and Li, 2019). Dysregulation of these compensatory mechanisms induces adverse cardiac remodeling, a series of maladaptive events leading to postinfarction myocardial injury (Santin et al, 2020).
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