Mitomycin induced the senescence of alveolar epithelial cells by targeting peroxiredoxin I

Area of Science:

• Pulmonary Toxicology
• Cellular Senescence
• Biochemistry

Background:

• Alveolar epithelial cell senescence is a hallmark of mitomycin-induced lung toxicity.
• The specific molecular target responsible for this senescence remains unidentified.

Purpose of the Study:

• To identify the direct molecular target of mitomycin that triggers alveolar epithelial cell senescence.
• To elucidate the mechanism linking mitomycin exposure to cellular senescence and lung toxicity.

Main Methods:

• Pulldown assay coupled with mass spectrometry to identify protein targets of mitomycin.
• Assays to measure peroxiredoxin I (Prdx I) activity, reactive oxygen species (ROS) levels, and kinase activation (MEK1/2-ERK1/2).
• Evaluation of cellular senescence markers and outcomes in response to Prdx I modulation and ROS scavenging.

Main Results:

• Peroxiredoxin I (Prdx I) was identified as the direct target of mitomycin-induced alveolar epithelial cell senescence.
• Mitomycin inhibits Prdx I peroxidase activity, leading to increased cellular ROS.
• ROS accumulation activates the MEK1/2-ERK1/2 pathway, increasing p53 expression and promoting senescence.
• Activating Prdx I or overexpressing it, along with ROS scavenging, attenuated mitomycin-induced senescence.

Conclusions:

• Peroxiredoxin I (Prdx I) is the primary target mediating mitomycin-induced alveolar epithelial cell senescence.
• Targeting Prdx I activity offers a potential therapeutic strategy to mitigate mitomycin-induced lung toxicity.