Journal
NATURE COMMUNICATIONS
Volume 11, Issue 1, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-13894-9
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Funding
- Horizon 2020 ERC Consolidator grant DeFiNER [GA64663]
- FP7 Marie Curie ITN aDDRess [GA316390]
- FP7 Marie Curie ITN CodeAge [GA316354]
- FP7 Marie Curie ITN Marriage [GA316964]
- Horizon 2020 Marie Curie ITN Chromatin3D [GA622934]
- Sante Foundation
- ELIDEK grant [1059]
- IKY postdoctoral research fellowship program - European Social Fund-ESF [MIS: 5001552]
- Greek government
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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 (Er1(F/-)) 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 Er1(F/-) animal sera and are secreted in macrophage media after DNA damage. The Er1(F/-) 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.
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