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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL067392-11
Application #
8468006
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Lin, Sara
Project Start
2001-04-01
Project End
2015-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
11
Fiscal Year
2013
Total Cost
$367,710
Indirect Cost
$129,710
Name
University of Rochester
Department
Pediatrics
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Kalifa, Lidza; Gewandter, Jennifer S; Staversky, Rhonda J et al. (2014) DNA double-strand breaks activate ATM independent of mitochondrial dysfunction in A549 cells. Free Radic Biol Med 75:30-9
Yee, Min; Buczynski, Bradley W; O'Reilly, Michael A (2014) Neonatal hyperoxia stimulates the expansion of alveolar epithelial type II cells. Am J Respir Cell Mol Biol 50:757-66
Buczynski, Bradley W; Maduekwe, Echezona T; O'Reilly, Michael A (2013) The role of hyperoxia in the pathogenesis of experimental BPD. Semin Perinatol 37:69-78
Gewandter, Jennifer S; Bambara, Robert A; O'Reilly, Michael A (2011) The RNA surveillance protein SMG1 activates p53 in response to DNA double-strand breaks but not exogenously oxidized mRNA. Cell Cycle 10:2561-7
Wu, Yu-Chieh M; O'Reilly, Michael A (2011) Bcl-X(L) is the primary mediator of p21 protection against hyperoxia-induced cell death. Exp Lung Res 37:82-91
Staversky, Rhonda J; Vitiello, Peter F; Yee, Min et al. (2010) Epithelial ablation of Bcl-XL increases sensitivity to oxygen without disrupting lung development. Am J Respir Cell Mol Biol 43:376-85
Lew, Betina J; Collins, Loretta L; O'Reilly, Michael A et al. (2009) Activation of the aryl hydrocarbon receptor during different critical windows in pregnancy alters mammary epithelial cell proliferation and differentiation. Toxicol Sci 111:151-62
Vitiello, Peter F; Wu, Yu-Chieh M; Staversky, Rhonda J et al. (2009) p21(Cip1) protects against oxidative stress by suppressing ER-dependent activation of mitochondrial death pathways. Free Radic Biol Med 46:33-41
Gewandter, Jennifer S; Staversky, Rhonda J; O'Reilly, Michael A (2009) Hyperoxia augments ER-stress-induced cell death independent of BiP loss. Free Radic Biol Med 47:1742-52
Gehen, S C; Staversky, R J; Bambara, R A et al. (2008) hSMG-1 and ATM sequentially and independently regulate the G1 checkpoint during oxidative stress. Oncogene 27:4065-74

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