Neurodegenerative disorders, including chemotherapy-induced cognitive impairment, are associated with neuronal mitochondrial dysfunction. Cisplatin, a commonly used chemotherapeutic, induces neuronal mitochondrial dysfunction in vivo and in vitro. Astrocytes are key players in supporting neuronal development, synaptogenesis, axonal growth, metabolism and, potentially mitochondrial health. We tested the hypothesis that astrocytes transfer healthy mitochondria to neurons after cisplatin treatment to restore neuronal health.We used an in vitro system in which astrocytes containing mito-mCherry-labeled mitochondria were co-cultured with primary cortical neurons damaged by cisplatin. Culture of primary cortical neurons with cisplatin reduced neuronal survival and depolarized neuronal mitochondrial membrane potential. Cisplatin induced abnormalities in neuronal calcium dynamics that were characterized by increased resting calcium levels, reduced calcium responses to stimulation with KCl, and slower calcium clearance. The same dose of cisplatin that caused neuronal damage did not affect astrocyte survival or astrocytic mitochondrial respiration. Co-culture of cisplatin-treated neurons with astrocytes increased neuronal survival, restored neuronal mitochondrial membrane potential, and normalized neuronal calcium dynamics especially in neurons that had received mitochondria from astrocytes which underlines the importance of mitochondrial transfer. These beneficial effects of astrocytes were associated with transfer of mitochondria from astrocytes to cisplatin-treated neurons. We show that siRNA-mediated knockdown of the Rho-GTPase Miro-1 in astrocytes reduced mitochondrial transfer from astrocytes to neurons and prevented the normalization of neuronal calcium dynamics.In conclusion, we showed that transfer of mitochondria from astrocytes to neurons rescues neurons from the damage induced by cisplatin treatment. Astrocytes are far more resistant to cisplatin than cortical neurons. We propose that transfer of functional mitochondria from astrocytes to neurons is an important repair mechanism to protect the vulnerable cortical neurons against the toxic effects of cisplatin.

中文翻译：

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顺铂治疗后星形胶质细胞通过线粒体转移挽救神经元健康。


神经退行性疾病，包括化疗引起的认知障碍，与神经元线粒体功能障碍有关。顺铂是一种常用的化疗药物，可在体内和体外诱导神经元线粒体功能障碍。星形胶质细胞是支持神经元发育、突触发生、轴突生长、新陈代谢以及潜在的线粒体健康的关键参与者。我们测试了星形胶​​质细胞在顺铂治疗后将健康的线粒体转移到神经元以恢复神经元健康的假设。我们使用了体外系统，其中含有 mito-mCherry 标记线粒体的星形胶质细胞与顺铂损伤的原代皮质神经元共培养。用顺铂培养原代皮质神经元会降低神经元存活率并使神经元线粒体膜电位去极化。顺铂诱导神经元钙动力学异常，其特征是静息钙水平增加、钙对 KCl 刺激的反应减少以及钙清除减慢。引起神经元损伤的相同剂量的顺铂并不影响星形胶质细胞的存活或星形胶质细胞的线粒体呼吸。顺铂处理的神经元与星形胶质细胞的共培养增加了神经元的存活，恢复了神经元线粒体膜电位，并使神经元钙动力学正常化，特别是在接受了星形胶质细胞线粒体的神经元中，这强调了线粒体转移的重要性。星形胶质细胞的这些有益作用与线粒体从星形胶质细胞转移到顺铂处理的神经元有关。我们发现，siRNA 介导的星形胶质细胞中 Rho-GTPase Miro-1 的敲低减少了星形胶质细胞到神经元的线粒体转移，并阻止了神经元钙动力学的正常化。总之，我们表明线粒体从星形胶质细胞转移到神经元可以挽救神经元免受顺铂治疗引起的损伤。星形胶质细胞对顺铂的抵抗力比皮质神经元强得多。我们认为，功能性线粒体从星形胶质细胞转移到神经元是保护脆弱的皮质神经元免受顺铂毒性作用的重要修复机制。