Equilibrative nucleoside transporter 2 modulates inosine catabolism to influence astrocyte metabolism and reactivity
Journal
Cell Reports
Journal Volume
44
Journal Issue
10
Start Page
116420
ISSN
2211-1247
Date Issued
2025-10-28
Author(s)
Chang, Ya-Gin
Lin, Hsin-Chuan
Chang, Ching-Pang
Lai, Hsing-Lin
Huang, Haoning
Chang, Pei-Rong
Wu, Ching-Wen
Ho, Chin-Jui
Chu, Ting
Chern, Yijuang
Abstract
Astrocytes display diverse reactive patterns in response to different stimuli, a phenomenon known as the heterogeneity of astrocyte reactivity. Although the mechanisms underlying these reactive states remain debated, energy metabolism is believed to play a key role in their regulation. Herein, we find that inosine acts as a vital energy source for astrocytes, particularly when activated by inflammatory stimuli. The absence of equilibrative nucleoside transporter 2 (Ent2), a key transporter of adenosine and inosine, leads to enhanced astrocyte reactivity in vitro and in vivo, affecting both their morphological and molecular profiles. Through metabolomic analysis and pharmacological approaches, we demonstrate that Ent2 regulates inosine efflux and is critical for maintaining proper energy balance in astrocytes. Furthermore, when inosine fails to enter energy-producing pathways, astrocyte reactivity is elevated. Overall, our findings demonstrate that inosine is a vital fuel for astrocytes under inflammatory stress and that Ent2 is the key transporter controlling astrocytes to utilize this fuel.
Subjects
ATP
CP: Cell biology
CP: Neuroscience
Ent2
energy homeostasis
inosine
reactive astrocyte
Type
journal article