| First Author | Goulielmaki E | Year | 2020 |
| Journal | Nat Commun | Volume | 11 |
| Issue | 1 | Pages | 42 |
| PubMed ID | 31896748 | Mgi Jnum | J:289930 |
| Mgi Id | MGI:6387545 | Doi | 10.1038/s41467-019-13894-9 |
| Citation | Goulielmaki E, et al. (2020) Tissue-infiltrating macrophages mediate an exosome-based metabolic reprogramming upon DNA damage. Nat Commun 11(1):42 |
| abstractText | 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. |
