Mitochondrial DNA integrity may be a determinant of endothelial barrier properties in oxidant-challenged rat lungs

Chouteau, J; Obiako, Boniface; Gorodnya, Olena M.; Pastukh, Viktor M.; Ruchko, Mykhaylo V.; Wright, A.; Wilson, Glenn L.; Gillespie, Mark N.

doi:10.1152/ajplung.00210.2011

Cited by 46 publications

(50 citation statements)

References 28 publications

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“…Another difference between mitochondrial and nuclear DNA particularly relevant to the present discussion is that mtDNA is ϳ50-fold more sensitive to oxidative damage (7,16,32,97). Reasons for this heightened sensitivity are not entirely known, but have been attributed to a comparatively simple process of mtDNA repair (mitochondria seem to contain only base excision repair whereas the nucleus has multiple, overlapping pathways) (8), and the prospect that the open structure of mtDNA is more accessible to DNA-damaging ROS.…”

Section: Sentinel Functions Of Mtdna In Pulmonary Vascular Cellsmentioning

confidence: 95%

“…In marked contrast to the lack of effect of hypoxia-induced mitochondrial ROS generation on mtDNA integrity, when cells or intact lung tissue are challenged with exogenous ROS the nuclear genome is largely spared of lesions whereas mtDNA is extensively damaged (7,16,32,97). One question that emerges from this interesting observation pertains to the biological value in having a mitochondrial genome sensitive to damage by exogenous oxidants whereas the nuclear genome is relatively resistant.…”

Section: Sentinel Functions Of Mtdna In Pulmonary Vascular Cellsmentioning

confidence: 99%

“…Early work showed that these fusion protein constructs prevented both hydrogen peroxide-induced mtDNA damage and increases in the vascular filtration coefficient in isolated perfused rat lungs (16). The Ogg1 construct also attenuated ventilatorinduced lung injury and mortality in mice (36) and hyperoxiainduced dysmorphogenesis in fetal rat lung explants (28).…”

Section: Sentinel Functions Of Mtdna In Pulmonary Vascular Cellsmentioning

confidence: 99%

See 2 more Smart Citations

Mitochondria in lung biology and pathology: more than just a powerhouse

Schumacker

Gillespie

Nakahira

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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165

164

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An explosion of new information about mitochondria reveals that their importance extends well beyond their time-honored function as the “powerhouse of the cell.” In this Perspectives article, we summarize new evidence showing that mitochondria are at the center of a reactive oxygen species (ROS)-dependent pathway governing the response to hypoxia and to mitochondrial quality control. The potential role of the mitochondrial genome as a sentinel molecule governing cytotoxic responses of lung cells to ROS stress also is highlighted. Additional attention is devoted to the fate of damaged mitochondrial DNA relative to its involvement as a damage-associated molecular pattern driving adverse lung and systemic cell responses in severe illness or trauma. Finally, emerging strategies for replenishing normal populations of mitochondria after damage, either through promotion of mitochondrial biogenesis or via mitochondrial transfer, are discussed.

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Section: Sentinel Functions Of Mtdna In Pulmonary Vascular Cellsmentioning

confidence: 95%

Section: Sentinel Functions Of Mtdna In Pulmonary Vascular Cellsmentioning

confidence: 99%

Section: Sentinel Functions Of Mtdna In Pulmonary Vascular Cellsmentioning

confidence: 99%

See 1 more Smart Citation

Mitochondria in lung biology and pathology: more than just a powerhouse

Schumacker

Gillespie

Nakahira

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

Self Cite

165

164

View full text Add to dashboard Cite

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“…Subcellular fractions were prepared as described previously [46] with minor modifications. In brief, PAECs were rinsed three times with PBS and two times with 0.25 M sucrose and 10 mM triethanolamine-acetic acid, pH 7.8, at room temperature and harvested in ice-cold 0.25 M sucrose, 1 mM EDTA, and 10 mM triethanolamine-acetic acid, pH 7.8.…”

Section: Methodsmentioning

confidence: 99%

Regulation of mitochondrial genome replication by hypoxia: The role of DNA oxidation in D-loop region

Pastukh

Gorodnya

Gillespie

et al. 2016

Free Radical Biology and Medicine

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Mitochondria of mammalian cells contain multiple copies of mitochondrial (mt) DNA. Although mtDNA copy number can fluctuate dramatically depending on physiological and pathophysiologic conditions, the mechanisms regulating mitochondrial genome replication remain obscure. Hypoxia, like many other physiologic stimuli that promote growth, cell proliferation and mitochondrial biogenesis, uses reactive oxygen species as signaling molecules. Emerging evidence suggests that hypoxia-induced transcription of nuclear genes requires controlled DNA damage and repair in specific sequences in the promoter regions. Whether similar mechanisms are operative in mitochondria is unknown. Here we test the hypothesis that controlled oxidative DNA damage and repair in the D-loop region of the mitochondrial genome are required for mitochondrial DNA replication and transcription in hypoxia. We found that hypoxia had little impact on expression of mitochondrial proteins in pulmonary artery endothelial cells, but elevated mtDNA content. The increase in mtDNA copy number was accompanied by oxidative modifications in the D-loop region of the mitochondrial genome. To investigate the role of this sequence-specific oxidation of mitochondrial genome in mtDNA replication, we overexpressed mitochondria-targeted 8-oxoguanine glycosylase Ogg1 in rat pulmonary artery endothelial cells, enhancing the mtDNA repair capacity of transfected cells. Overexpression of Ogg1 resulted in suppression of hypoxia-induced mtDNA oxidation in the D-loop region and attenuation of hypoxia-induced mtDNA replication. Ogg1 overexpression also reduced binding of mitochondrial transcription factor A (TFAM) to both regulatory and coding regions of the mitochondrial genome without altering total abundance of TFAM in either control or hypoxic cells. These observations suggest that oxidative DNA modifications in the D-loop region during hypoxia are important for increased TFAM binding and ensuing replication of the mitochondrial genome.

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“…Whereas reactive species are generated by multiple cellular sources, including mitochondria, endoplasmic reticulum, peroxisomes as well as by nitric oxide synthases (NOS) and NADPH oxidases (NOX), the majority of ROS are produced by the electron transport chain via oxidative phosphorylation (5, 57). Excess ROS produced by the mitochondria can alter the enzyme function and damage the mitochondrial DNA, which may impact the mitochondrial efficiency and potentially amplify the mitochondrial ROS production (19,28). Increased mitochondrial oxidative stress triggers programmed cell death and apoptosis through BAX activation and cytochrome C release (23,124).…”

Section: Reactive Oxygen and Nitrogen Species Generation And Lung Injurymentioning

confidence: 99%

Developmental Regulation of Antioxidant Enzymes and Their Impact on Neonatal Lung Disease

Berkelhamer

Farrow

2014

Antioxidants & Redox Signaling

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Significance: Deficient antioxidant defenses and compromised ability to respond to oxidative stress burden the immature lung. Routine neonatal therapies can cause increased oxidative stress with subsequent injury to the premature lung. Novel therapeutic approaches to protect the premature lung are greatly needed. Recent Advances: Live cell imaging with targeted redox probes allows for the measurement of subcellular oxidative stress and for comparisons of oxidative stress across development. Comprehension of subcellular and cell-typespecific responses to oxidative stress may influence the targeting of future antioxidant therapies. Critical Issues: Challenges remain in identifying the optimal cellular targets, degree of enzyme activity, and appropriate antioxidant therapy. Further, the efficacy of delivering exogenous antioxidants to specific cell types or subcellular compartments remains under investigation. Treatment with a nonselective antioxidant could unintentionally compromise cellular function or impact cellular defense mechanisms and homeostasis. Future Directions: Genetic and/or biomarker screening may identify infants at the greatest risk for oxidative lung injury and guide the use of more selective antioxidant therapies. Novel approaches to the delivery of antioxidant enzymes may allow cell type-or cellular organelle-specific therapy. Improved comprehension of the antioxidant enzyme regulation across cell type, cell compartment, gender, and developmental stage is critical to the design and optimization of therapy.

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Mitochondrial DNA integrity may be a determinant of endothelial barrier properties in oxidant-challenged rat lungs

Cited by 46 publications

References 28 publications

Mitochondria in lung biology and pathology: more than just a powerhouse

Mitochondria in lung biology and pathology: more than just a powerhouse

Regulation of mitochondrial genome replication by hypoxia: The role of DNA oxidation in D-loop region

Developmental Regulation of Antioxidant Enzymes and Their Impact on Neonatal Lung Disease

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