Mitochondrial Fission Mediated Cigarette Smoke-induced Pulmonary Endothelial Injury

Am J Respir Cell Mol Biol. 2020 Nov;63(5):637-651. doi: 10.1165/rcmb.2020-0008OC.


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.

Keywords: apoptosis; cigarette smoke; endothelial permeability; mitochondrial fission/fusion; mitophagy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis
  • Capillary Permeability
  • Cell Respiration
  • Dynamins / metabolism
  • Endothelial Cells / pathology*
  • Lung / blood supply
  • Lung / pathology*
  • Male
  • Mice
  • Microvessels / pathology
  • Mitochondria / pathology
  • Mitochondrial Dynamics*
  • Mitophagy
  • Models, Biological
  • Oxidative Stress
  • Protein Transport
  • Rats
  • Smoking / adverse effects*


  • Dnm1l protein, mouse
  • Dnm1l protein, rat
  • Dynamins