Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany.
Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany.
J Trace Elem Med Biol. 2021 May;65:126711. doi: 10.1016/j.jtemb.2021.126711. Epub 2021 Jan 14.
Being an essential trace element, copper is involved in diverse physiological processes. However, excess levels might lead to adverse effects. Disrupted copper homeostasis, particularly in the brain, has been associated with human diseases including the neurodegenerative disorders Wilson and Alzheimer's disease. In this context, astrocytes play an important role in the regulation of the copper homeostasis in the brain and likely in the prevention against neuronal toxicity, consequently pointing them out as a potential target for the neurotoxicity of copper. Major toxic mechanisms are discussed to be directed against mitochondria probably via oxidative stress. However, the toxic potential and mode of action of copper in astrocytes is poorly understood, so far.
In this study, excess copper levels affecting human astrocytic cell model and their involvement in the neurotoxic mode of action of copper, as well as, effects on the homeostasis of other trace elements (Mn, Fe, Ca and Mg) were investigated.
Copper induced substantial cytotoxic effects in the human astrocytic cell line following 48 h incubation (EC: 250 μM) and affected mitochondrial function, as observed via reduction of mitochondrial membrane potential and increased ROS production, likely originating from mitochondria. Moreover, cellular GSH metabolism was altered as well. Interestingly, not only cellular copper levels were affected, but also the homeostasis of other elements (Ca, Fe and Mn) were disrupted.
One potential toxic mode of action of copper seems to be effects on the mitochondria along with induction of oxidative stress in the human astrocytic cell model. Moreover, excess copper levels seem to interact with the homeostasis of other essential elements such as Ca, Fe and Mn. Disrupted element homeostasis might also contribute to the induction of oxidative stress, likely involved in the onset and progression of neurodegenerative disorders. These insights in the toxic mechanisms will help to develop ideas and approaches for therapeutic strategies against copper-mediated diseases.
铜作为一种必需的微量元素，参与多种生理过程。然而，过量的铜可能会导致不良反应。铜稳态失衡，特别是在大脑中，与包括神经退行性疾病威尔逊病和阿尔茨海默病在内的人类疾病有关。在这种情况下，星形胶质细胞在大脑中铜稳态的调节中起着重要作用，可能在预防神经元毒性方面起着重要作用，因此将它们作为铜神经毒性的潜在靶点。主要的毒性机制被认为是针对线粒体的，可能是通过氧化应激。然而，到目前为止，铜在星形胶质细胞中的毒性潜力和作用方式还知之甚少。
在这项研究中，研究了影响人星形胶质细胞模型的过量铜水平及其在铜神经毒性作用模式中的作用，以及对其他微量元素（锰、铁、钙和镁）稳态的影响。
铜在 48 小时孵育后（EC：250 μM）对人星形胶质细胞系产生了显著的细胞毒性作用，并影响了线粒体功能，如线粒体膜电位降低和 ROS 产生增加，这可能源于线粒体。此外，细胞内 GSH 代谢也发生了改变。有趣的是，不仅细胞内铜水平受到影响，而且其他元素（钙、铁和锰）的稳态也被打乱。
铜在人星形胶质细胞模型中的一种潜在毒性作用模式似乎是对线粒体的影响，以及氧化应激的诱导。此外，过量的铜水平似乎与其他必需元素（如钙、铁和锰）的稳态相互作用。元素稳态的破坏也可能导致氧化应激的诱导，这可能与神经退行性疾病的发生和发展有关。这些关于毒性机制的见解将有助于为针对铜介导疾病的治疗策略提供思路和方法。
