Carbon ion therapy is a promising modality in radiotherapy to treat tumors[1],however,a potential risk of induction of late normal tissue damage should still be investigated and protected.The aim of the present study was to explore the long-term cognitive deficits provoked by a high-linear energy transfer(high-LET)carbon ions in mice by targeting to hippocampus which plays a crucial role in memory and learning.Our data showed that,one month after 4 Gy carbon ion exposure,carbon ion irradiation conspicuously resulted in the impaired cognitive performance,neurodegeneration and neuronal cell death,as well as the reduced mitochondrial integrity,the disrupted activities of tricarboxylic acid cycle flux and electron transport chain,and the depressed antioxidant defense system,consequently leading to a decline of ATP production and persistent oxidative damage in the hippocampus region(Fig.1(a)and(b)).Mechanistically,we demonstrated the disruptions of mitochondrial homeostasis and redox balance typically characterized by the disordered mitochondrial dynamics,mitophagy and glutathione redox couple,which is closely associated with the inhibitions of PINK1 and NRF2 signaling pathway as the key regulators of molecular responses in the context of neurotoxicity and neurodegenerative disorders.Most importantly,we found that administration with melatonin as a mitochondria-targeted antioxidant promoted the PINK1 accumulation on the mitochondrial membrane,and augmented the NRF2 accumulation and translocation(Fig.1(c)and(d)).
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