Proton Radiation-Induced Cognitive Impairment via Disruption of Hippocampal Neuronal Mitophagic Homeostasis

Background: Proton radiation is both a core component of the space radiation environment and a pivotal modality for precision clinical tumor radiotherapy. Proton exposure can impair cognitive, learning and memory functions, representing a common concern in the fields of deep space aerospace medicine and clinical radiotherapy. Nevertheless, the cellular and molecular regulatory mechanisms underlying proton-induced cognitive impairment remain incompletely elucidated. Methods: In vivo and in vitro injury models were established via 100 MeV proton radiation. Specifically, an in vivo model of proton radiation-induced cognitive injury was constructed using C57BL/6J mice (male), and an in vitro radiation injury model was established with HT22 hippocampal neuronal cells to systematically investigate the molecular mechanism of cognitive impairment caused by proton radiation. Results: Proton radiation induced a persistent decline in learning and memory capacity in mice, triggered systemic oxidative stress, caused metabolic disturbances of multiple neurotransmitters in the hippocampus, and induced structural mitochondrial damage and decreased mitochondrial membrane potential in hippocampal neurons, suggesting that mitochondria are the key subcellular target of its neurotoxicity. Proton radiation induced oxidative stress in hippocampal neurons. Hyperactivation of mTORC1 inhibited the kinase activity of ULK1 by phosphorylating its Ser757 residue and downregulated ULK1 protein levels, resulting in mitophagy dysfunction and mitophagic flux blockade. Persistent severe oxidative stress prevented damaged mitochondria from being cleared via mitophagy and activated the apoptotic cascade, ultimately leading to hippocampal neuronal death and cognitive impairment. Conclusions: This study reveals the molecular mechanism by which proton radiation induces mitophagy dysfunction and hippocampal neuronal apoptosis and subsequently triggers cognitive impairment, providing a new theoretical basis and potential intervention targets for the prevention and treatment of neurocognitive complications associated with space radiation exposure and clinical radiotherapy.