Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Post Box No. 80, Lucknow, 226 001, Uttar Pradesh, India.
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201 002, Uttar Pradesh, India.
J Mol Neurosci. 2022 Jun;72(6):1413-1427. doi: 10.1007/s12031-022-02008-8. Epub 2022 Apr 27.
Mitochondrial dysfunction and nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) are the major sources of augmentation in free radical generation leading to neurodegeneration. Although NADPH oxidase involvement is reported in zinc (Zn)-induced neurodegeneration, contribution of the mitochondrial dysfunction and its association with NADPH oxidase are not known. Therefore, the study was aimed to decipher the role of mitochondrial dysfunction and its link with NADPH oxidase in Zn-induced Parkinsonism. Zn reduced the motor activities, the number of tyrosine hydroxylase (TH)-positive neurons, and level of TH protein. Conversely, Zn increased the mitochondrial reactive oxygen species (ROS) production, lipid peroxidation (LPO), and superoxide dismutase (SOD) activity and reduced the mitochondrial membrane potential and catalytic activities of complex I and III. Zn also attenuated B-cell lymphoma-2 (Bcl-2) and pro-caspase 9/3 levels and augmented the translocation of cytosolic Bcl-2 associated X (Bax) protein to the mitochondria and cytochrome c release into cytosol from the mitochondria. Cyclosporine A, a mitochondrial outer membrane transition pore inhibitor and apocynin, a NADPH oxidase inhibitor, independently, ameliorated the Zn-induced changes. Similarly, Zn reduced cell viability through mitochondrial dysfunction and apoptosis in human neuroblastoma SH-SY5Y cells, which were notably normalized in the presence of cyclosporine or apocynin. The results demonstrate that mitochondrial dysfunction contributes to Zn-induced neurodegeneration, which could be partially aided by the NADPH oxidase.
线粒体功能障碍和烟酰胺腺嘌呤二核苷酸磷酸氧化酶（NADPH 氧化酶）是自由基生成增加导致神经退行性变的主要来源。虽然 NADPH 氧化酶参与了锌（Zn）诱导的神经退行性变，但线粒体功能障碍的贡献及其与 NADPH 氧化酶的关系尚不清楚。因此，本研究旨在阐明线粒体功能障碍及其与 NADPH 氧化酶在 Zn 诱导的帕金森病中的作用。Zn 降低了运动活动、酪氨酸羟化酶（TH）阳性神经元数量和 TH 蛋白水平。相反，Zn 增加了线粒体活性氧（ROS）的产生、脂质过氧化（LPO）和超氧化物歧化酶（SOD）活性，降低了线粒体膜电位和复合物 I 和 III 的催化活性。Zn 还减弱了 B 细胞淋巴瘤-2（Bcl-2）和前半胱天冬酶 9/3 的水平，并增加了细胞质 Bcl-2 相关 X（Bax）蛋白向线粒体的易位和细胞色素 c 从线粒体向细胞质的释放。环孢菌素 A，一种线粒体外膜过渡孔抑制剂和 apocynin，一种 NADPH 氧化酶抑制剂，独立地改善了 Zn 诱导的变化。同样，Zn 通过线粒体功能障碍和人神经母细胞瘤 SH-SY5Y 细胞中的细胞凋亡降低了细胞活力，而在存在环孢菌素或 apocynin 的情况下，这些变化明显得到了正常化。结果表明，线粒体功能障碍导致 Zn 诱导的神经退行性变，NADPH 氧化酶可能部分有助于这一过程。
