Περίληψη:
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.
Συγγραφείς:
Goulielmaki, Evi
Ioannidou, Anna
Tsekrekou, Maria
Stratigi,
Kalliopi
Poutakidou, Ioanna K.
Gkirtzimanaki, Katerina and
Aivaliotis, Michalis
Evangelou, Konstantinos
Topalis, Pantelis
and Altmueller, Janine
Gorgoulis, Vassilis G.
Chatzinikolaou,
Georgia
Garinis, George A.
