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Published on: October 19, 2013
Mitochondrial DNA Variations Modulate Alveolar Epithelial Mitochondrial Function and Oxidative Stress in Newborn Mice
Insights
Mitochondrial DNA variations impact lung injury in premature infants with bronchopulmonary dysplasia (BPD). Different mtDNA types affect mitochondrial function and mitophagy, influencing disease severity and protein expression in infants.
Area of Science:
- Mitochondrial Biology and Genetics
- Neonatal Lung Disease Pathogenesis
- Oxidative Stress and Inflammation
Background:
- Oxidative stress is a key factor in bronchopulmonary dysplasia (BPD), a prevalent chronic lung disease in preterm infants.
- Mitochondrial DNA (mtDNA) variations are implicated in disorders involving oxidative stress, potentially influencing BPD development.
- Previous studies demonstrated that mtDNA variations modulate hyperoxia-induced lung injury in a BPD mouse model.
Approach:
- Investigated the impact of mtDNA variations on mitochondrial function, including mitophagy, in alveolar epithelial cells (AT2) using mitochondrial-nuclear exchange (MNX) mice.
- Assessed oxidant and inflammatory stress, transcriptomic profiles, and expression of key proteins (PINK1, Parkin, SIRT3) in mouse lung tissue and BPD infants.
- Compared mitochondrial function and stress responses between mice with C57 and C3H mtDNA during hyperoxia exposure.
Key Points:
- Mice with C57 mtDNA exhibited impaired mitochondrial bioenergetics, reduced inner membrane potential, increased permeability, and heightened oxidant stress in AT2 cells compared to C3H mtDNA.
- Hyperoxia-exposed lungs with C57 mtDNA showed elevated pro-inflammatory cytokines and altered KEGG pathways related to inflammation and signaling.
- Mitophagy was significantly reduced by hyperoxia, with a more pronounced decrease in AT2 cells and lung fibroblasts from mice with C57 mtDNA.
- Black infants with BPD displayed lower expression of PINK1, Parkin, and SIRT3 compared to White infants, suggesting ethnic variations in disease predisposition.
Conclusions:
- mtDNA variations and mito-nuclear interactions play a significant role in modulating susceptibility and severity of neonatal lung injury in BPD.
- Differences in mtDNA haplogroups may contribute to ethnic disparities observed in BPD outcomes.
- Further investigation into mito-nuclear interactions is crucial for uncovering novel pathogenic mechanisms and therapeutic targets for BPD.
Abstract:
Oxidative stress is an important contributor to bronchopulmonary dysplasia (BPD), a form of chronic lung disease that is the most common morbidity in very preterm infants. Mitochondrial functional differences due to inherited and acquired mutations influence the pathogenesis of disorders in which oxidative stress plays a critical role. We previously showed using mitochondrial-nuclear exchange (MNX) mice that mitochondrial DNA (mtDNA) variations modulate hyperoxia-induced lung injury severity in a model of BPD. In this study, we studied the effects of mtDNA variations on mitochondrial function including mitophagy in alveolar epithelial cells (AT2) from MNX mice. We also investigated oxidant and inflammatory stress as well as transcriptomic profiles in lung tissue in mice and expression of proteins such as PINK1, Parkin and SIRT3 in infants with BPD. Our results indicate that AT2 from mice with C57 mtDNA had decreased mitochondrial bioenergetic function and inner membrane potential, increased mitochondrial membrane permeability and were exposed to higher levels of oxidant stress during hyperoxia compared to AT2 from mice with C3H mtDNA. Lungs from hyperoxia-exposed mice with C57 mtDNA also had higher levels of pro-inflammatory cytokines compared to lungs from mice with C3H mtDNA. We also noted changes in KEGG pathways related to inflammation, PPAR and glutamatergic signaling, and mitophagy in mice with certain mito-nuclear combinations but not others. Mitophagy was decreased by hyperoxia in all mice strains, but to a greater degree in AT2 and neonatal mice lung fibroblasts from hyperoxia-exposed mice with C57 mtDNA compared to C3H mtDNA. Finally, mtDNA haplogroups vary with ethnicity, and Black infants with BPD had lower levels of PINK1, Parkin and SIRT3 expression in HUVEC at birth and tracheal aspirates at 28 days of life when compared to White infants with BPD. These results indicate that predisposition to neonatal lung injury may be modulated by variations in mtDNA and mito-nuclear interactions need to be investigated to discover novel pathogenic mechanisms for BPD.
