Fazzari Maria, Audano Matteo, Lunghi Giulia, Di Biase Erika, Loberto Nicoletta, Mauri Laura, Mitro Nico, Sonnino Sandro, Chiricozzi Elena
Department of Medical Biotechnology and Translational Medicine, University of Milano, Via Fratelli Cervi 93, 20090, Segrate (MI), Italy.
Department of Pharmacological and Biomolecular Sciences, University of Milano, Via Balzaretti 9, 20133, Milan (MI), Italy.
Glycoconj J. 2020 Jun;37(3):293-306. doi: 10.1007/s10719-020-09920-4. Epub 2020 Apr 8.
The crucial role of ganglioside GM1 in the regulation of neural homeostasis has been assessed by several studies. Recently we shed new light on the molecular basis underlying GM1 effects demonstrating that GM1 oligosaccharide directly binds TrkA receptor and triggers MAPK pathway activation leading to neuronal differentiation and protection. Following its exogenous administration, proteomic analysis revealed an increased expression of proteins involved in several biochemical mechanisms, including mitochondrial bioenergetics. Based on these data, we investigated the possible effect of GM1 oligosaccharide administration on mitochondrial function. We show that wild-type Neuro2a cells exposed to GM1 oligosaccharide displayed an increased mitochondrial density and an enhanced mitochondrial activity together with reduced reactive oxygen species levels. Interestingly, using a Neuro2a model of mitochondrial dysfunction, we found an increased mitochondrial oxygen consumption rate as well as increased complex I and II activities upon GM1 oligosaccharide administration. Taken together, our data identify GM1 oligosaccharide as a mitochondrial regulator that by acting at the plasma membrane level triggers biochemical signaling pathway inducing mitochondriogenesis and increasing mitochondrial activity. Although further studies are necessary, the capability to enhance the function of impaired mitochondria points to the therapeutic potential of the GM1 oligosaccharide for the treatment of pathologies where these organelles are compromised, including Parkinson's disease.
多项研究评估了神经节苷脂GM1在调节神经内环境稳定中的关键作用。最近，我们揭示了GM1作用的分子基础，表明GM1寡糖直接结合TrkA受体并触发MAPK途径激活，从而导致神经元分化和保护。在其外源给药后，蛋白质组学分析显示参与多种生化机制（包括线粒体生物能量学）的蛋白质表达增加。基于这些数据，我们研究了GM1寡糖给药对线粒体功能的可能影响。我们发现，暴露于GM1寡糖的野生型Neuro2a细胞显示出线粒体密度增加、线粒体活性增强以及活性氧水平降低。有趣的是，使用线粒体功能障碍的Neuro2a模型，我们发现给予GM1寡糖后线粒体氧消耗率增加以及复合体I和II的活性增加。综上所述，我们的数据确定GM1寡糖是一种线粒体调节剂，它通过作用于质膜水平触发生化信号通路，诱导线粒体生成并增加线粒体活性。尽管还需要进一步研究，但增强受损线粒体功能的能力表明GM1寡糖在治疗这些细胞器受损的疾病（包括帕金森病）方面具有治疗潜力。
