CNC-Center for Neuroscience and Cell Biology and CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal.
Ph.D. Programme in Biomedicine and Experimental Biology (PDBEB), Institute for Interdisciplinary Research, University of Coimbra, 3004-504 Coimbra, Portugal.
Int J Mol Sci. 2023 Feb 22;24(5):4339. doi: 10.3390/ijms24054339.
Mitochondria play a key role in regulating host metabolism, immunity and cellular homeostasis. Remarkably, these organelles are proposed to have evolved from an endosymbiotic association between an alphaproteobacterium and a primitive eukaryotic host cell or an archaeon. This crucial event determined that human cell mitochondria share some features with bacteria, namely cardiolipin, N-formyl peptides, mtDNA and transcription factor A, that can act as mitochondrial-derived damage-associated molecular patterns (DAMPs). The impact of extracellular bacteria on the host act largely through the modulation of mitochondrial activities, and often mitochondria are themselves immunogenic organelles that can trigger protective mechanisms through DAMPs mobilization. In this work, we demonstrate that mesencephalic neurons exposed to an environmental alphaproteobacterium activate innate immunity through toll-like receptor 4 and Nod-like receptor 3. Moreover, we show that mesencephalic neurons increase the expression and aggregation of alpha-synuclein that interacts with mitochondria, leading to their dysfunction. Mitochondrial dynamic alterations also affect mitophagy which favors a positive feedback loop on innate immunity signaling. Our results help to elucidate how bacteria and neuronal mitochondria interact and trigger neuronal damage and neuroinflammation and allow us to discuss the role of bacterial-derived pathogen-associated molecular patterns (PAMPs) in Parkinson's disease etiology.
线粒体在调节宿主代谢、免疫和细胞内稳态方面发挥着关键作用。值得注意的是，这些细胞器被认为是由α变形菌和原始真核宿主细胞或古菌之间的内共生关联进化而来的。这一关键事件决定了人类细胞线粒体与细菌共享一些特征，即心磷脂、N-甲酰肽、mtDNA 和转录因子 A，它们可以作为线粒体衍生的损伤相关分子模式 (DAMP)。细胞外细菌对宿主的影响在很大程度上是通过调节线粒体活性来实现的，而线粒体本身常常是免疫原性的细胞器，可以通过 DAMPs 的动员来触发保护机制。在这项工作中，我们证明暴露于环境α变形菌的中脑神经元通过 Toll 样受体 4 和 Nod 样受体 3 激活先天免疫。此外，我们还表明，中脑神经元增加了与线粒体相互作用的α-突触核蛋白的表达和聚集，导致其功能障碍。线粒体动力学的改变也会影响线粒体自噬，从而促进先天免疫信号的正反馈环。我们的研究结果有助于阐明细菌和神经元线粒体如何相互作用并引发神经元损伤和神经炎症，并允许我们讨论细菌衍生的病原体相关分子模式 (PAMP) 在帕金森病发病机制中的作用。
