Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China; Ministry of Education Key Lab for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China.
Center for Translational Medicine, Wuhan Union Hospital, Huazhong University of Science and Technology, Wuhan, PR China.
Redox Biol. 2020 Sep;36:101626. doi: 10.1016/j.redox.2020.101626. Epub 2020 Jun 30.
As a widely acknowledged environmental pollutant, lead (Pb) exhibits neurological toxicity primarily due to the vulnerability of neural system. It is suggested that Pb could perturb mitochondrial function, triggering the following disturbance of cellular homeostasis. Here, we focused on the role of mitochondrial dynamics in Pb-induced cell damage. Pb exposure enhanced mitochondrial fragmentation and elevated p-Drp1 (s616) level in a reactive oxygen species (ROS) dependent manner, leading to cell death and energy shortage. By applying metformin, an AMP-activated protein kinase (AMPK) activator, these impairments could be alleviated via activation of AMPK, validated by experiments of pharmacological inhibition of AMPK. Further investigation confirmed that nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor managing antioxidative function, and its downstream antioxidant detoxifying enzyme were activated by metformin, resulting in the inhibition of the Pb-caused oxidative stress. Moreover, Nrf2 mediated the protection of metformin against mitochondrial fragmentation induced by Pb exposure, while knockdown of Nrf2 abrogated the protective effect. Finally, the treatment of Mdivi-1, a mitochondrial fission inhibitor, reversed Pb-triggered cell death, revealing that excessive mitochondrial fission is detrimental. To conclude, metformin could ameliorate Pb-induced mitochondrial fragmentation via antioxidative effects originated from AMPK/Nrf2 pathway activation, promoting energy supply and cell survival.
作为一种广泛认可的环境污染物，铅（Pb）主要因其对神经系统的易感性而表现出神经毒性。有研究表明，铅可能会扰乱线粒体功能，引发细胞内稳态的以下紊乱。在这里，我们专注于线粒体动力学在 Pb 诱导的细胞损伤中的作用。Pb 暴露以依赖于活性氧（ROS）的方式增强线粒体碎片化和 p-Drp1（s616）水平的升高，导致细胞死亡和能量短缺。通过应用二甲双胍，一种 AMP 激活的蛋白激酶（AMPK）激活剂，可以通过激活 AMPK 来缓解这些损伤，这通过 AMPK 的药理学抑制实验得到了验证。进一步的研究证实，核因子红细胞 2 相关因子 2（Nrf2），一种管理抗氧化功能的转录因子，及其下游抗氧化解毒酶被二甲双胍激活，导致 Pb 引起的氧化应激受到抑制。此外，Nrf2 介导了二甲双胍对 Pb 暴露引起的线粒体碎片化的保护作用，而 Nrf2 的敲低则消除了这种保护作用。最后，线粒体分裂抑制剂 Mdivi-1 的处理逆转了 Pb 触发的细胞死亡，表明过度的线粒体分裂是有害的。总之，二甲双胍可以通过激活 AMPK/Nrf2 通路的抗氧化作用来改善 Pb 诱导的线粒体碎片化，从而促进能量供应和细胞存活。
