Neonatal Hyperoxia Activates Activating Transcription Factor 4 to Stimulate Folate Metabolism and Alveolar Epithelial...

Area of Science:

• Neonatal physiology
• Cell biology
• Respiratory medicine

Background:

• Oxygen supplementation is crucial for preterm infants but can disrupt lung development.
• Alveolar epithelial type 2 (AT2) cell proliferation is vital for lung repair but can be dysregulated by hyperoxia.
• The precise mechanisms by which hyperoxia affects AT2 cell proliferation remain unclear.

Purpose of the Study:

• To investigate the molecular mechanisms by which hyperoxia induces aberrant AT2 cell proliferation in newborn mice.
• To identify key signaling pathways and molecular targets involved in hyperoxia-induced AT2 cell overgrowth.

Main Methods:

• RNA-sequencing of AT2 cells isolated from newborn mice exposed to hyperoxia.
• Analysis of gene expression related to folate metabolism and serine synthesis.
• Investigating the role of activating transcription factor 4 (ATF4) and mitochondrial oxidative stress.

Main Results:

• Hyperoxia upregulates mitochondrial methylenetetrahydrofolate dehydrogenase 2 and serine synthesis genes in AT2 cells.
• This upregulation is selectively mediated by the stress-responsive transcription factor ATF4.
• MitoTEMPO, a mitochondrial scavenger, inhibited hyperoxia-induced ATF4 activation and AT2 cell proliferation.
• ATF4 and methylenetetrahydrofolate dehydrogenase are present in hyperplastic AT2 cells in human and baboon bronchopulmonary dysplasia models.

Conclusions:

• Hyperoxia triggers aberrant AT2 cell proliferation through ATF4-mediated regulation of mitochondrial metabolism.
• Dampening mitochondrial oxidative stress and inhibiting ATF4 activation are potential therapeutic strategies for neonatal lung diseases characterized by AT2 cell hyperplasia.
• Findings offer insights into preventing or treating bronchopulmonary dysplasia by targeting specific molecular pathways.