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| Item Type: | Article |
|---|---|
| Title: | Tissue-infiltrating macrophages mediate an exosome-based metabolic reprogramming upon DNA damage |
| Creators Name: | Goulielmaki, E., Ioannidou, A., Tsekrekou, M., Stratigi, K., Poutakidou, I.K., Gkirtzimanaki, K., Aivaliotis, M., Evangelou, K., Topalis, P., Altmüller, J., Gorgoulis, V.G., Chatzinikolaou, G. and Garinis, G.A. |
| Abstract: | 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. |
| Keywords: | DNA Damage, DNA Repair, DNA-Binding Proteins, Endonucleases, Exosomes, Gene Expression Regulation, Glucose, Glucose Transporter Type 1, Inflammation, Macrophages, Neuropeptides, rab GTP-Binding Proteins, rac1 GTP-Binding Protein, TOR Serine-Threonine Kinases, Transgenic Mice, Animals, Mice |
| Source: | Nature Communications |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Volume: | 11 |
| Number: | 1 |
| Page Range: | 42 |
| Date: | 2 January 2020 |
| Official Publication: | https://doi.org/10.1038/s41467-019-13894-9 |
| PubMed: | View item in PubMed |
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