Integrated Evidence for Lysosomal Dysfunction-Mediated Iron Dysregulation induced by PM₂.₅ Exposure

Area of Science:

• Environmental Health
• Toxicology
• Cell Biology

Background:

• Ambient fine particulate matter (PM2.5) poses significant risks to human health, particularly affecting the respiratory system.
• Iron (Fe) homeostasis is crucial for cellular function, and its dysregulation is implicated in various diseases.
• Understanding the interplay between PM2.5 exposure and Fe metabolism is vital for mitigating adverse health outcomes.

Purpose of the Study:

• To investigate the role of iron homeostasis disruption in PM2.5-induced lung injury.
• To elucidate the mechanisms by which PM2.5 affects Fe metabolism and cellular function in the lungs.
• To identify potential biomarkers and therapeutic targets for PM2.5-related pulmonary damage.

Main Methods:

• Epidemiological analysis of serum ferritin light chain (FTL) levels in relation to residential PM2.5 concentrations.
• In vivo studies using a PM2.5 analogue (1,4-NQ-BC) in rat lungs to assess FTL, autophagy, and Fe levels.
• In vitro studies using RAW264.7 cells to examine the effects of 1,4-NQ-BC on Fe transport, autophagy, and lysosomal function.
• Investigating the role of lysosomal dysfunction in PM-induced Fe deficiency using transcription factor EB overexpression.

Main Results:

• Serum FTL levels were positively correlated with PM2.5 concentrations, indicating PM2.5-induced disruption of Fe homeostasis.
• PM2.5 analogue exposure increased FTL and impaired autophagy flux in rat lungs.
• In vitro, PM2.5 analogue reduced Fe2+ but increased total Fe, activated autophagy, yet impaired lysosomal function and autophagic flux.
• Lysosomal dysfunction was identified as a novel mechanism contributing to PM-induced Fe2+ deficiency.

Conclusions:

• PM2.5 exposure disrupts iron homeostasis, leading to Fe2+ deficiency and contributing to lung injury.
• Lysosomal damage plays a critical role in PM-induced Fe2+ deficiency.
• FTL and lysosomal function may serve as sensitive biomarkers and potential therapeutic targets for pulmonary injury associated with PM2.5 exposure.