Ameliorating mitochondrial dysfunction restores carbon ion-induced cognitive deficits via co-activation of NRF2 and PINK1 signaling pathway.
Ameliorating mitochondrial dysfunction restores carbon ion-induced cognitive deficits via co-activation of NRF2 and PINK1 signaling pathway.
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改善线粒体功能障碍通过NRF2和PINK1信号通路的共激活来恢复碳离子诱导的认知缺陷。
DOI：
10.1016/j.redox.2018.04.012
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发表时间：
2018-07
期刊：
影响因子：
11.4
通讯作者：
Zhang H
中科院分区：
文献类型：
--
作者：
Liu Y;Yan J;Sun C;Li G;Li S;Zhang L;Di C;Gan L;Wang Y;Zhou R;Si J;Zhang H
碳离子治疗是一种很有前途的放射治疗肿瘤的方式，然而，诱导晚期正常组织损伤的潜在风险仍然需要研究和保护。本研究的目的是探讨高线性能量转移（high-LET）碳离子通过靶向在记忆和学习中起关键作用的海马引起的小鼠长期认知障碍。我们的数据表明，4戈伊碳离子照射后1个月，碳离子照射显著导致认知能力受损、神经元变性和神经元细胞死亡，以及线粒体完整性降低、三羧酸循环通量和电子传递链活性中断、抗氧化防御系统受到抑制，从而导致海马区ATP产生的下降和持续的氧化损伤。从机制上讲，我们证明了线粒体稳态和氧化还原平衡的破坏，其典型特征是线粒体动力学紊乱、线粒体自噬和谷胱甘肽氧化还原对，这与PINK 1和NRF 2信号通路的抑制密切相关，PINK 1和NRF 2信号通路是神经毒性和神经退行性疾病背景下分子反应的关键调节因子。最重要的是，我们发现，褪黑素作为一种靶向抗氧化剂的管理促进了PINK 1在线粒体膜上的积累，并增加了NRF 2的积累和易位。此外，褪黑激素明显增强了NRF 2和PINK 1之间的分子相互作用。此外，在小鼠海马神经元细胞中，NRF 2/PINK 1的过表达显著地保护海马神经元免受碳离子引起的毒性损伤。因此，这些数据表明，通过共调节NRF 2和PINK 1来缓解持续的线粒体功能障碍和氧化应激可能负责恢复高LET碳离子照射小鼠模型中的认知障碍。
Carbon ion therapy is a promising modality in radiotherapy to treat tumors, 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. 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. Moreover, melatonin pronouncedly enhanced the molecular interplay between NRF2 and PINK1. Furthermore, in the mouse hippocampal neuronal cells, overexpression of NRF2/PINK1 strikingly protected the hippocampal neurons from carbon ion-elicited toxic insults. Thus, these data suggest that alleviation of the sustained mitochondrial dysfunction and oxidative stress through co-modulation of NRF2 and PINK1 may be in charge of restoration of the cognitive impairments in a mouse model of high-LET carbon ion irradiation.
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影响因子：
3.5
作者：
Branca, Caterina;Ferreira, Eric;Oddo, Salvatore
通讯作者：
Oddo, Salvatore
辐射引起的脑损伤的分子，细胞和功能效应：综述。
影响因子：
5.6
作者：
Balentova S;Adamkov M
通讯作者：
Adamkov M
影响因子：
6.1
作者：
Guo C;Sun L;Chen X;Zhang D
通讯作者：
Zhang D
DOI：
10.3791/2920
发表时间：
2011-07-20
期刊：
Journal of visualized experiments : JoVE
影响因子：
--
作者：
Bromley-Brits, Kelley;Deng, Yu;Song, Weihong
通讯作者：
Song, Weihong
影响因子：
2.4
作者：
Itoh K;Ye P;Matsumiya T;Tanji K;Ozaki T
通讯作者：
Ozaki T