Tissue-infiltrating macrophages mediate an exosome-based metabolic reprogramming upon DNA damage.
Evi GoulielmakiAnna IoannidouMaria TsekrekouKalliopi StratigiIoanna K PoutakidouKaterina GkirtzimanakiMichalis AivaliotisKonstantinos EvangelouPantelis TopalisJanine AltmüllerVassilis G GorgoulisGeorgia ChatzinikolaouGeorge A GarinisPublished in: Nature communications (2020)
DNA damage and metabolic disorders are intimately linked with premature disease onset but the underlying mechanisms remain poorly understood. Here, we show that persistent DNA damage accumulation in tissue-infiltrating macrophages carrying an ERCC1-XPF DNA repair defect (Er1F/-) triggers Golgi dispersal, dilation of endoplasmic reticulum, autophagy and exosome biogenesis leading to the secretion of extracellular vesicles (EVs) in vivo and ex vivo. Macrophage-derived EVs accumulate in Er1F/- animal sera and are secreted in macrophage media after DNA damage. The Er1F/- EV cargo is taken up by recipient cells leading to an increase in insulin-independent glucose transporter levels, enhanced cellular glucose uptake, higher cellular oxygen consumption rate and greater tolerance to glucose challenge in mice. We find that high glucose in EV-targeted cells triggers pro-inflammatory stimuli via mTOR activation. This, in turn, establishes chronic inflammation and tissue pathology in mice with important ramifications for DNA repair-deficient, progeroid syndromes and aging.
Keyphrases
- dna damage
- dna repair
- endoplasmic reticulum
- oxidative stress
- induced apoptosis
- dna damage response
- cell cycle arrest
- high glucose
- endoplasmic reticulum stress
- blood glucose
- endothelial cells
- signaling pathway
- type diabetes
- estrogen receptor
- cell death
- high fat diet induced
- breast cancer cells
- wild type
- glycemic control
- skeletal muscle
- drug induced
- weight loss