Tissue-infiltrating macrophages mediate an exosome-based metabolic reprogramming upon DNA damage

Area of Science:

• Molecular Biology
• Cell Biology
• Metabolic Disorders

Background:

• DNA damage and metabolic disorders are linked to premature aging.
• The mechanisms connecting DNA repair defects to metabolic dysfunction are unclear.

Purpose of the Study:

• To investigate how DNA damage in macrophages affects cellular processes and systemic metabolism.
• To explore the role of extracellular vesicles (EVs) in mediating these effects.

Main Methods:

• Utilized mice with a DNA repair defect (ERCC1-XPF) in macrophages.
• Analyzed EV secretion, cargo, and uptake by recipient cells.
• Assessed glucose uptake, oxygen consumption, and inflammatory responses in vivo and ex vivo.

Main Results:

• Macrophage DNA damage induced Golgi dispersal, ER dilation, autophagy, and EV biogenesis.
• EVs from damaged macrophages altered glucose transporter levels and uptake in recipient cells.
• EV-mediated glucose uptake activated mTOR, leading to inflammation and tissue pathology.

Conclusions:

• Macrophage-derived EVs propagate metabolic dysfunction and inflammation following DNA damage.
• This pathway has implications for understanding aging, progeroid syndromes, and age-related diseases.