Mechanism of Mitochondrial Dysfunction in COPD

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SUMMARY Chronic Obstructive Pulmonary Disease (COPD) is the third leading cause of chronic morbidity and mortality, both in the United States (affecting an estimated 23 million people) and globally. Cigarette smoke (CS), the most important etiological risk factor for the development of COPD/emphysema, causes lung injurious and damaging responses. These effects include mitochondrial dysfunction (i.e., reduced mitochondrial membrane potential and increased mitochondrial reactive oxygen species [mtROS] generation), and defective mitophagy (removal of damaged mitochondria from a cell prior to cell death). Our preliminary data show that CS-induced defective mitophagy is associated with perinuclear localization of dysfunctional mitochondria and disruption of telomere-shelterin complex (a complex which protects telomeres from DNA damage) in lung cells. We further show that the transfer of mitochondria occurs from mesenchymal stem cells (MSCs) into senesced lung epithelial cells, and protects against CS-induced senescence-associated secretory phenotype and mitochondrial dysfunction in vitro and in vivo. However, the cellular and molecular mechanisms for CS-induced mitophagy impairment and shelterin complex mitochondrial translocation, as well as their roles in cellular senescence during the development of COPD/emphysema are not known. We hypothesize that CS-induced mitochondrial dysfunction leads to defective mitophagy by disrupting the protective shelterin telomere capping protein complex, and that healthy mitochondrial transfer into damaged lung epithelial cells protects against CS- induced injurious responses in COPD/emphysema. To test these hypotheses, we will pursue the following three Specific Aims in this 4-year R01. (1) Determine the molecular mechanisms underlying CS-induced mitochondrial dysfunction and defective mitophagy. (2) Determine the mechanism of disrupted shelterin complex in CS-induced mitochondrial dysfunction and impaired mitophagy. (3) Determine the protective and/or restorative influence of Miro1 (mitochondrial Rho-GTPase)-dependent fresh/healthy mitochondrial transfer during CS-induced pulmonary emphysema. The outcome of this proposal will unravel novel molecular mechanisms for CS-induced mitochondrial dysfunction, shelterin complex disruption, and senescence in lung injurious and damaging responses during the pathogenesis of COPD/emphysema. The proposed studies have considerable translational potential as they will determine the mechanisms whereby possible attenuation of the telomere shelterin complex and/or Miro1-mediated mitochondria transfer can be utilized as novel therapeutic targets for the treatment/management of COPD/emphysema.