Abstract
BackgroundExcessive proliferation of pulmonary artery smooth muscle cells (PASMCs) is the main cause of hypoxic pulmonary hypertension (PH), and mitochondrial homeostasis plays a crucial role. However, the specific molecular regulatory mechanism of mitochondrial function in PASMCs remains unclear.MethodsIn this study, using the CCK8 assay, EdU incorporation, flow cytometry, Western blotting, co-IP, mass spectrometry, electron microscopy, immunofluorescence, Seahorse extracellular flux analysis and echocardiography, we investigated the specific involvement of apoptosis-inducing factor (AIF), a mitochondrial oxidoreductase in regulating mitochondrial energy metabolism and mitophagy in PASMCs.ResultsIn vitro, AIF deficiency in hypoxia leads to impaired oxidative phosphorylation and increased glycolysis and ROS release because of the loss of mitochondrial complex I activity. AIF was also downregulated and ubiquitinated under hypoxia leading to the abnormal occurrence of mitophagy and autophagy through its interaction with ubiquitin protein UBA52. In vivo, treatment with the adeno-associated virus vector to overexpress AIF protected pulmonary vascular remodeling from dysfunctional and abnormal proliferation.ConclusionsTaken together, our results identify AIF as a potential therapeutic target for PH and reveal a novel posttranscriptional regulatory mechanism in hypoxia-induced mitochondrial dysfunction.
Highlights
Pulmonary hypertension (PH) is a fatal cardiovascular and respiratory system disease characterized by a progressive increase in the mean pulmonary artery pressure and symptoms of exertional dyspnea, resulting in right ventricular failure and death [1, 2]
We found for the first time that ubiquitinated and decreased apoptosis-inducing factor (AIF) expression induced by hypoxia resulted in mitochondrial respiratory chain impairment with abnormal mitochondrial metabolism, elevated mitophagy and autophagy, and eventually increased cell proliferation
Hypoxia induces mitochondrial complex I lesions and AIF downregulation To verify mitochondrial dysfunction in hypoxia, we first assessed the activities of mitochondrial respiratory chain complexes in lung tissue
Summary
Pulmonary hypertension (PH) is a fatal cardiovascular and respiratory system disease characterized by a progressive increase in the mean pulmonary artery pressure and symptoms of exertional dyspnea, resulting in right ventricular failure and death [1, 2]. The inactivity of mitochondrial complex III leads to mitochondrial respiratory chain dysfunction, reduces ATP and elevates ROS production, which promotes the development of Parkinson’s disease [19]. The decrease in mitochondrial respiratory chain activity increases of ROS generation and cardiolipin oxidation, causing mitochondrial dysfunction, which further aggravates myocardial ischemia reperfusion injury [20]. These findings highlight that mitochondrial homeostasis is crucial in the progression of various diseases. Excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) is the main cause of hypoxic pulmonary hypertension (PH), and mitochondrial homeostasis plays a crucial role. The specific molecular regulatory mechanism of mitochondrial function in PASMCs remains unclear
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