Mitochondrial Dysfunction Contributes to Alveolar Developmental Arrest in Hyperoxia-Exposed Mice

Abstract

This study investigated whether mitochondrial dysfunction contributes to alveolar developmental arrest in a mouse model of bronchopulmonary dysplasia (BPD). To induce BPD, 3-day-old mice were exposed to 75% O 2 . Mice were studied at two time points of hyperoxia (72 h or 2 wk) and after 3 weeks of recovery in room air (RA). A separate cohort of mice was exposed to pyridaben, a complex-I (C-I) inhibitor, for 72 hours or 2 weeks. Alveolarization was quantified by radial alveolar count and mean linear intercept methods. Pulmonary mitochondrial function was defined by respiration rates, ATP-production rate, and C-I activity. At 72 hours, hyperoxic mice demonstrated significant inhibition of C-I activity, reduced respiration and ATP production rates, and significantly decreased radial alveolar count compared with controls. Exposure to pyridaben for 72 hours, as expected, caused significant inhibition of C-I and ADP-phosphorylating respiration. Similar to hyperoxic littermates, these pyridaben-exposed mice exhibited significantly delayed alveolarization compared with controls. At 2 weeks of exposure to hyperoxia or pyridaben, mitochondrial respiration was inhibited and associated with alveolar developmental arrest. However, after 3 weeks of recovery from hyperoxia or 2 weeks after 72 hours of exposure to pyridaben alveolarization significantly improved. In addition, there was marked normalization of C-I and mitochondrial respiration. The degree of hyperoxia-induced pulmonary simplification and recovery strongly (r 2 5 0.76) correlated with C-I activity in lung mitochondria. Thus, the arrest of alveolar development induced by either hyperoxia or direct inhibition of mitochondrial oxidative phosphorylation indicates that bioenergetic failure to maintain normal alveolar development is one of the fundamental mechanisms responsible for BPD.

Epithelial Ablation of Bcl-XL Increases Sensitivity to Oxygen without Disrupting Lung Development

“…This may reflect the oxidation of mitochondrial DNA, because 8-oxoguanine staining in mice colocalized to cytochrome-C oxidase subunit 1. Intriguingly, mitochondrial dysfunction was recently associated with arrested lung development in newborn mice exposed to hyperoxia, and Bcl-X L functioned to maintain mitochondrial homeostasis (52,53). Although levels of Bcl-X L were similar in newborn and adult mice (data not shown), targeting additional levels to developing lungs exposed to hyperoxia may provide a novel therapy for preventing BPD.…”

Glycogen synthase kinase-3β/β-catenin signaling regulates neonatal lung mesenchymal stromal cell myofibroblastic differentiation

“…Two-to three-day-old wild-type C57BL/6J mice (Jackson Laboratories, Bar Harbor, ME) were exposed to air or 75% oxygen for 14 days using a polypropylene chamber coupled to an oxygen controller and sensor (BioSpherix, Lacona, NY) (23). Dams were exchanged between air and hyperoxia daily.…”

Activation of TNFR1 ectodomain shedding by mitochondrial Ca2+ determines the severity of inflammation in mouse lung microvessels

“…All assays were conducted on mitochondria isolated from lung tissue according to previously reported methods (67).…”