Autophagy, TERT, and mitochondrial dysfunction in hyperoxia.

Area of Science:

• Pulmonary medicine
• Cellular biology
• Biochemistry

Background:

• Hyperoxia (high oxygen) is crucial for treating hypoxia but causes lung injury by increasing reactive oxygen species (ROS).
• Autophagy/mitophagy and telomerase reverse transcriptase (TERT) are implicated in cellular protection against ROS-induced damage.
• The interplay between TERT and autophagy in hyperoxia-induced pulmonary endothelial injury remains unclear.

Purpose of the Study:

• To investigate the interaction between autophagy/mitophagy and TERT in hyperoxia-induced mitochondrial dysfunction and pulmonary injury.
• To determine the protective roles of TERT and autophagy in cultured rat lung microvascular endothelial cells (RLMVECs) and rat lungs exposed to hyperoxia.

Main Methods:

• RLMVECs and rat lungs were exposed to hyperoxia in vitro and in vivo.
• Assessed mitochondrial damage (TOMM20, MTT), inflammation (MPO, IL-1β, TLR9), autophagy markers (Beclin-1, LC3B-II/1, p62), and TERT expression.
• Evaluated the effects of TERT or autophagy activation/inhibition on mitochondrial function and transendothelial resistance.

Main Results:

• Hyperoxia induced mitochondrial damage, inflammation, impaired autophagy signaling, and decreased TERT expression in rat lungs.
• Mitochondrial damage was exacerbated in rats lacking TERT, leading to reduced cellular proliferation.
• Activation of TERT or autophagy individually mitigated mitochondrial damage and preserved endothelial barrier function; autophagy activation was protective in both WT and TERT-deficient rats.

Conclusions:

• Autophagy activation, with or without TERT, mitigates mitochondrial dysfunction and barrier integrity loss during hyperoxia.
• Hyperoxia impairs autophagosome clearance, suggesting cross-talk between TERT and autophagy pathways.
• Stimulating autophagy is a promising therapeutic strategy to prevent hyperoxia-induced mitochondrial damage and maintain lung endothelial barrier function.