Molecular Neurotoxicology and Cell Integrity Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226001, India.
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
Mol Neurobiol. 2022 Aug;59(8):4761-4775. doi: 10.1007/s12035-022-02862-y. Epub 2022 May 25.
The regulatory network of mitochondrial biogenesis and dynamics is vital for mitochondrial functions and cellular homeostasis. Any impairment in the mitochondrial network leads to neurodegenerative disorders. Our earlier studies suggest that environmental toxicant Bisphenol-A (BPA) exposure reduces neurogenesis by abnormal mitochondrial dynamics and mitochondrial biogenesis through impairment of mitochondrial fission factor dynamin-related protein (DRP1) and mitochondrial import protein GFER, which leads to demyelination, neurodegeneration, and cognitive deficits in the rats. In the present study, we found that chronic BPA exposure reduces PGC-1α levels (master regulator of mitochondrial biogenesis), alters mitochondrial localization of DRP1 and GFER, and reduces the number of PGC-1α/NeuN and PGC-1α/β-tubulin neurons in the rat hippocampus, suggesting reduced PGC-1α-mediated neurogenesis. Nicotinamide significantly increased PGC-1α protein levels, PGC-1α/NeuN+ co-labeled cells in BPA-treated rat hippocampus and PGC-1α/β-tubulin+ co-labeled cells in neuron culture derived from hippocampal neural stem cells. Interestingly, PGC-1α upregulation by nicotinamide also resulted in increased GFER levels and restored mitochondrial localization of GFER (increased GFER/TOMM20 co-labeled cells) in vitro and in vivo following BPA treatment. Nicotinamide also reduced DRP1 levels and prevented DRP1 mitochondrial localization in BPA-treated neuronal cultures and hippocampus, suggesting reduced mitochondrial fission. This resulted in reduced cytochrome c levels in neuronal culture and reduced hippocampal neurodegeneration (reduced caspase-3/NeuN co-labeled neurons) following nicotinamide treatment in BPA-treated group. Consequently, activation of PGC-1α by nicotinamide restored BPA-mediated cognitive deficits in rats. Results suggest that the treatment of nicotinamide has therapeutic potential and rescues BPA-mediated neuronal death and cognitive deficits by upregulating the PGC-1α and GFER-DRP1 link, thus balancing mitochondrial homeostasis.
线粒体生物发生和动力学的调节网络对线粒体功能和细胞内稳态至关重要。线粒体网络的任何损伤都会导致神经退行性疾病。我们之前的研究表明，环境毒物双酚 A（BPA）暴露通过损伤线粒体分裂因子相关蛋白（DRP1）和线粒体输入蛋白 GFER 导致异常的线粒体动力学和线粒体生物发生，从而减少神经发生，导致大鼠脱髓鞘、神经退行性变和认知缺陷。在本研究中，我们发现慢性 BPA 暴露降低了 PGC-1α 水平（线粒体生物发生的主要调节因子），改变了 DRP1 和 GFER 的线粒体定位，并减少了大鼠海马区 PGC-1α/NeuN 和 PGC-1α/β-微管蛋白神经元的数量，提示 PGC-1α 介导的神经发生减少。烟酰胺显著增加了 BPA 处理大鼠海马区 PGC-1α 蛋白水平、PGC-1α/NeuN+共标记细胞和海马神经干细胞来源神经元培养物中 PGC-1α/β-微管蛋白+共标记细胞的数量。有趣的是，烟酰胺上调 PGC-1α 还导致 GFER 水平升高，并恢复了 BPA 处理后体外和体内 GFER 的线粒体定位（增加 GFER/TOMM20 共标记细胞）。烟酰胺还降低了 DRP1 水平并阻止了 BPA 处理神经元培养物和海马区的 DRP1 线粒体定位，提示线粒体分裂减少。这导致神经元培养物中细胞色素 c 水平降低，BPA 处理组烟酰胺处理后海马区神经退行性变减少（减少 caspase-3/NeuN 共标记神经元）。因此，烟酰胺激活 PGC-1α 可恢复 BPA 介导的大鼠认知缺陷。结果表明，烟酰胺的治疗具有潜在的治疗作用，并通过上调 PGC-1α 和 GFER-DRP1 连接来挽救 BPA 介导的神经元死亡和认知缺陷，从而平衡线粒体稳态。
