Castellano-González Gloria, Pichaud Nicolas, Ballard J William O, Bessede Alban, Marcal Helder, Guillemin Gilles J
MND and Neurodegenerative Diseases Research Group, Australian School of Advanced Medicine (ASAM), Macquarie University, Sydney, Australia.
Department of Biological and Environmental Sciences, University of Gothenburg, Göteborg, Sweden.
Oncotarget. 2016 Feb 16;7(7):7426-40. doi: 10.18632/oncotarget.6863.
Mitochondrial dysfunction and resulting energy impairment have been identified as features of many neurodegenerative diseases. Whether this energy impairment is the cause of the disease or the consequence of preceding impairment(s) is still under discussion, however a recovery of cellular bioenergetics would plausibly prevent or improve the pathology. In this study, we screened different natural molecules for their ability to increase intracellular adenine triphosphate purine (ATP). Among them, epigallocatechin-3-gallate (EGCG), a polyphenol from green tea, presented the most striking results. We found that it increases ATP production in both human cultured astrocytes and neurons with different kinetic parameters and without toxicity. Specifically, we showed that oxidative phosphorylation in human cultured astrocytes and neurons increased at the level of the routine respiration on the cells pre-treated with the natural molecule. Furthermore, EGCG-induced ATP production was only blocked by sodium azide (NaN3) and oligomycin, inhibitors of cytochrome c oxidase (CcO; complex IV) and ATP synthase (complex V) respectively. These findings suggest that the EGCG modulates CcO activity, as confirmed by its enzymatic activity. CcO is known to be regulated differently in neurons and astrocytes. Accordingly, EGCG treatment is acting differently on the kinetic parameters of the two cell types. To our knowledge, this is the first study showing that EGCG promotes CcO activity in human cultured neurons and astrocytes. Considering that CcO dysfunction has been reported in patients having neurodegenerative diseases such as Alzheimer's disease (AD), we therefore suggest that EGCG could restore mitochondrial function and prevent subsequent loss of synaptic function.
线粒体功能障碍及由此导致的能量损伤已被确认为多种神经退行性疾病的特征。然而，这种能量损伤是疾病的病因还是先前损伤的结果仍在讨论中，不过细胞生物能量学的恢复有望预防或改善病理状况。在本研究中，我们筛选了不同天然分子增加细胞内三磷酸腺苷嘌呤（ATP）的能力。其中，表没食子儿茶素-3-没食子酸酯（EGCG），一种来自绿茶的多酚，呈现出最显著的结果。我们发现它能在人培养的星形胶质细胞和神经元中增加ATP生成，具有不同的动力学参数且无毒性。具体而言，我们表明在用该天然分子预处理的细胞的常规呼吸水平上，人培养的星形胶质细胞和神经元中的氧化磷酸化增加。此外，EGCG诱导的ATP生成仅被叠氮化钠（NaN3）和寡霉素阻断，它们分别是细胞色素c氧化酶（CcO；复合体IV）和ATP合酶（复合体V）的抑制剂。这些发现表明EGCG调节CcO活性，这在其酶活性中得到证实。已知CcO在神经元和星形胶质细胞中的调节方式不同。因此，EGCG处理对这两种细胞类型的动力学参数的作用不同。据我们所知，这是第一项表明EGCG促进人培养的神经元和星形胶质细胞中CcO活性的研究。鉴于在患有神经退行性疾病如阿尔茨海默病（AD）的患者中已报道CcO功能障碍，我们因此认为EGCG可以恢复线粒体功能并预防随后的突触功能丧失。
