ADP-ribose triggers neuronal ferroptosis by rewiring purine and pyrimidine metabolism
Escrito por Haoqi Ni, Yingying He, Peng Cui, Hebing Chen, Guoqing Lv, Huiyan Lei, Feng Wang, Qichuan ZhuGe, Baodong Chen, Ling Liang, Yong Zhang, Fuping You y Lin Yuan
Publicado
14 de mayo de 2021
Servidor
bioRxiv
Resumen
Hyperactivation of NAD+ -consuming pathways frequently occurs in neurological diseases, however therapies replenishing NAD+ levels show limited therapeutic efficacy, indicating more complex underlying pathophysiology. Here, we delineate a pathogenic link between ADP-ribose —a product of NAD+ consumption—and a metabolic rewiring-dependent form of neuronal ferroptosis. We demonstrate that oxidative stress induces neurons to produce ADP-ribose through the PARP1-PARG axis. ADP-ribose directly binds and inhibits the equilibrative nucleoside transporter ENT2, remodelingde novo purine and pyrimidine synthesis by hyperactivating the inosine-hypoxanthine-xanthine oxidase and glutamine-dihydroorotate-dihydroorotate dehydrogenase axes. This overproduces superoxide radicals and drives lipid peroxidation and neuronal ferroptosis. Elevated ADP-ribose levels were observed in neurological disease models, and acute ADP-ribose exposure severely reduced mouse brain neuronsin vivo . Critically, interventions blocking ADP-ribose signaling alleviated cognitive decline in mouse intracerebral hemorrhage models. Our findings characterize ADP-ribose signaling as linking NAD+ consumption to neuronal ferroptosis, and provide a theraputic strategy for neuropathologies involving NAD+ consumption and oxidative stress.
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