Premature exposure to oxygen is a major risk factor for bronchopulmonary dysplasia (BPD), a chronic form of lung disease frequently seen in neonates that is characterized as an arrest in lung development. Although the therapeutic use of exogenous surfactant and milder ventilation strategies has reduced mortality, children and adolescents born prematurely have reduced lung function, increased susceptibility to respiratory viral infections, and age-associated increases in blood pressure. Hence there is an urgent need to understand how oxygen permanently disrupts growth of the developing lung. Recent studies suggest damage to mitochondria is a component of oxygen-induced newborn lung disease because elevated levels of oxygen (hyperoxia) suppress mitochondrial respiration and damage mitochondrial DNA. To determine whether cells activate retrograde signaling back to the nucleus to control gene expression in response to mitochondrial DNA damage, epithelial cells were infected with retroviruses expressing enzymes that cause strand breaks in mitochondrial or nuclear DNA. Like hyperoxia, damage to mitochondrial or nuclear DNA stimulated expression of the tumor suppressor protein p53. In contrast, mitochondrial targeting of an enzyme that only cuts nuclear DNA failed to activate p53, but did so when targeted to the nucleus. When activated by mitochondrial DNA damage, p53 stimulated expression of nuclear genes that inhibited cell growth and enhanced cell survival. These findings suggest the cell reacts to mitochondrial DNA damage with a classic nuclear DNA damage response, and that this response inhibits cell growth, perhaps in anticipation of impending mitochondrial dysfunction and energy depletion. Based upon these findings, we now propose to test the hypothesis that mitochondrial DNA damage is a component of how hyperoxia activates p53 signaling and disrupts postnatal lung development. We will test this hypothesis using novel retroviruses and transgenic mice capable of conditionally damaging mitochondrial DNA in respiratory epithelial cells. Understanding how cells respond specifically to oxygen-induced mitochondrial DNA damage is highly significant because it could lead to new therapeutic opportunities for reducing oxygen-toxicity to the developing lung as well as age-related diseases attributed to oxygen toxicity.

Public Health Relevance

Recent studies suggest mitochondrial damage is a component of hyperoxia-induced newborn lung disease because hyperoxia suppresses mitochondrial respiration and oxidizes mitochondrial DNA. Hence, understanding how cells respond to oxygen-induced mitochondrial DNA damage is highly significant because it could lead to new therapeutic opportunities for reducing oxygen-toxicity to the developing lung as well as age-related diseases attributed to oxygen toxicity.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Lung Injury, Repair, and Remodeling Study Section (LIRR)
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Lin, Sara
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University of Rochester
Schools of Dentistry
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Resseguie, Emily A; Brookes, Paul S; O'Reilly, Michael A (2017) SMG-1 kinase attenuates mitochondrial ROS production but not cell respiration deficits during hyperoxia. Exp Lung Res 43:229-239
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