Nicotinamide Mononucleotide Prevents Cisplatin-Induced Mitochondrial Defects in Cortical Neurons Derived from Human Induced Pluripotent Stem Cells.
Nicotinamide Mononucleotide Prevents Cisplatin-Induced Mitochondrial Defects in Cortical Neurons Derived from Human Induced Pluripotent Stem Cells.
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DOI：
10.3233/bpl-220143
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Jang, Mi-Hyeon
中科院分区：
文献类型：
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作者：
Rashid, Mohammad Abdur;Oliveros, Alfredo;Kim, Yu Shin;Jang, Mi-Hyeon
化疗引起的认知障碍（CICI）是化疗的一种神经毒性副作用，目前尚无有效的治疗方法。使用顺铂（一种基于铂的化疗药物）以及源自人诱导多能细胞（iPSC）的兴奋性皮质神经元来模拟CICI，我们最近的研究表明，脑NAD+代谢的失调有助于顺铂诱导的神经发生和认知功能障碍，这可以通过给予NAD+前体烟酰胺单核苷酸（NMN）来预防。然而，目前尚不清楚顺铂如何导致神经源性功能障碍以及NMN预防顺铂诱导的认知障碍的机制。鉴于线粒体功能障碍被认为在年龄相关的神经退行性疾病和化疗诱导的神经毒性中起着重要作用，我们试图探索NMN是否通过减弱顺铂诱导的线粒体损伤来预防化疗相关的神经毒性。我们证明，顺铂诱导神经元DNA损伤，增加线粒体活性氧（ROS）的产生，并减少ATP的产生，所有这些都表明氧化DNA损伤和线粒体功能缺陷。超微结构分析表明，顺铂引起的人皮层神经元嵴膜的完整性和基质肿胀的损失。值得注意的是，NMN预处理可以防止顺铂诱导的人类皮质神经元线粒体缺陷。我们的研究结果表明，增加线粒体氧化应激和功能缺陷发挥关键作用，顺铂诱导的神经毒性。因此，NMN可能是一种有效的治疗策略，以防止顺铂诱导的对线粒体的有害影响，使这种细胞器的一个关键因素，在改善顺铂诱导的认知障碍。
Chemotherapy-induced cognitive impairment (CICI) is a neurotoxic side effect of chemotherapy that has yet to have an effective treatment. Using cisplatin, a platinum-based chemotherapy together with excitatory cortical neurons derived from human induced pluripotent cells (iPSCs) to model of CICI, our recent study demonstrated that dysregulation of brain NAD+ metabolism contributes to cisplatin-induced impairments in neurogenesis and cognitive function, which was prevented by administration of the NAD+ precursor, nicotinamide mononucleotide (NMN). However, it remains unclear how cisplatin causes neurogenic dysfunction and the mechanism by which NMN prevents cisplatin-induced cognitive impairment. Given that mitochondrial dysfunction is thought to play a prominent role in age-related neurodegenerative disease and chemotherapy-induced neurotoxicity, we sought to explore if NMN prevents chemotherapy-related neurotoxicity by attenuating cisplatin-induced mitochondrial damage. We demonstrate that cisplatin induces neuronal DNA damage, increases generation of mitochondrial reactive oxygen species (ROS) and decreases ATP production, all of which are indicative of oxidative DNA damage and mitochondrial functional defects. Ultrastructural analysis revealed that cisplatin caused loss of cristae membrane integrity and matrix swelling in human cortical neurons. Notably, pretreatment with NMN prevents cisplatin-induced defects in mitochondria of human cortical neurons. Our results suggest that increased mitochondrial oxidative stress and functional defects play key roles in cisplatin-induced neurotoxicity. Thus, NMN may be an effective therapeutic strategy to prevent cisplatin-induced deleterious effects on mitochondria, making this organelle a key factor in amelioration of cisplatin-induced cognitive impairments.