Mitochondrial Fission Mediated Cigarette Smoke–induced Pulmonary Endothelial Injury
| Autor: | Junsuk Ko, Gaurav Choudhary, Alexis White, Qing Lu, Sharon Rounds, Zhengke Wang, Thilo S. Lange, Xing Wang |
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| Rok vydání: | 2020 |
| Předmět: |
Dynamins
Male 0301 basic medicine Pulmonary and Respiratory Medicine FIS1 Cell Respiration Clinical Biochemistry MFN2 Apoptosis Mitochondrion Lung injury medicine.disease_cause Mitochondrial Dynamics Models Biological Capillary Permeability Mice 03 medical and health sciences 0302 clinical medicine Mitophagy medicine Animals Lung Molecular Biology Original Research Chemistry Smoking Endothelial Cells Cell Biology Mitochondria Rats Cell biology Oxidative Stress Protein Transport 030104 developmental biology 030228 respiratory system mitochondrial fusion Microvessels Mitochondrial fission Oxidative stress |
| Zdroj: | Am J Respir Cell Mol Biol |
| ISSN: | 1535-4989 1044-1549 |
| DOI: | 10.1165/rcmb.2020-0008oc |
| Popis: | Cigarette smoke (CS) exposure increases the risk for acute respiratory distress syndrome in humans and promotes alveolar–capillary barrier permeability and acute lung injury in animal models. However, the underlying mechanisms are not well understood. Mitochondrial fusion and fission are essential for mitochondrial homeostasis in health and disease. In this study, we hypothesized that CS caused endothelial injury via an imbalance of mitochondrial fusion and fission and resultant mitochondrial oxidative stress and dysfunction. We noted that CS altered mitochondrial morphology by shortening mitochondrial networks and causing perinuclear accumulation of damaged mitochondria in primary rat lung microvascular endothelial cells. We also found that CS increased mitochondrial fission likely by decreasing Drp1-S637 and increasing FIS1, Drp1-S616 phosphorylation, mitochondrial translocation, and tetramerization and reduced mitochondrial fusion likely by decreasing Mfn2 in lung microvascular endothelial cells and mouse lungs. CS also caused aberrant mitophagy, increased mitochondrial oxidative stress, and reduced mitochondrial respiration. An inhibitor of mitochondrial fission and a mitochondria-specific antioxidant prevented CS-induced increased endothelial barrier dysfunction and apoptosis. Our data suggest that excessive mitochondrial fission and resultant oxidative stress are essential mediators of CS-induced endothelial injury and that inhibition of mitochondrial fission and mitochondria-specific antioxidants may be useful therapeutic strategies for CS-induced endothelial injury and associated pulmonary diseases. |
| Databáze: | OpenAIRE |
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