Effects of Hyperoxia on Mitochondrial Homeostasis: Are Mitochondria the Hub for Bronchopulmonary Dysplasia?

Abstract

Mitochondria are involved in energy metabolism and redox reactions in the cell. Emerging data indicate that mitochondria play an essential role in physiological and pathological processes of neonatal lung development. Mitochondrial damage due to exposure to high concentrations of oxygen is an indeed important factor for simplification of lung structure and development of bronchopulmonary dysplasia (BPD), as reported in humans and rodent models. Here, we comprehensively review research that have determined the effects of oxygen environment on alveolar development and morphology, summarize changes in mitochondria under high oxygen concentrations, and discuss several mitochondrial mechanisms that may affect cell plasticity and their effects on BPD. Thus, the pathophysiological effects of mitochondria may provide insights into targeted mitochondrial and BPD therapy.

Keywords: alveolarisation; bronchopulmonary dysplasia; hyperoxia; lung development; mitochondria.

FIGURE 1

Proposed mechanisms of mitochondrial homeostasis and lung development under hyperxia. Hyperoxia exposure can simplify the lung structure of premature infants, reduce the number of alveoli and reduce the number of microvascular in the lungs compared with the normal group. High oxygen can affect the plasticity of mitochondria and influence BPD.

FIGURE 2

Summary of the major pathophysiological events contributing to mitochondrial dysfunction in hyperoxia-exposed neonatal lung. Oxygen affects the mechanism of alveolar morphology mainly through mitochondrial dysfunction. Altered ROS levels and mitochondrial metabolism in alveolar cells and mitochondrial homeostasis disorders are involved in the occurrence of BPD. These states of dysfunction are interdependent and can further form loops that influence each other. They can also be simultaneously affected by controlling the quality of mitochondria. In addition, mitochondria in alveolar cells communicate with the nucleus by regulating several transcription factors, such as Nrf2-AREs, HIF-1α, and SIRTs, and undergo epigenetic modifications. All these aspects provide possible evidence for the important role of mitochondria in BPD. ROS, reactive oxygen species; AT2, alveolar type 2; BPD, bronchopulmonary dysplasia; LBs, Lamellar corpuscle; ATP, adenosine triphosphate; OPA1, optic atrophy 1; Drp1, dynamin-related protein 1; Fis1, mitochondrial fission protein 1; Mfn1, mitofusins protein 1; NOX, NADPH oxidase; TFAM, mitochondrial transcription factor A; TFBM, mitochondrial transcription factor B; PGC-1α, peroxisome proliferator-activated receptor γ coactivator 1-α.