Oxidative stress develops as a response to injury and reflects a breach in the cell’s antioxidant capacity. Therefore, the fine-tuning of reactive oxygen species (ROS) generation is crucial for preserving cell’s homeostasis. Mitochondria are a major source and an immediate target of ROS. Under different stimuli, including oxidative stress and impaired quality control, mitochondrial constituents (e.g., mitochondrial DNA, mtDNA) are displaced toward intra- or extracellular compartments. However, the mechanisms responsible for mtDNA unloading remain largely unclear. While shuttling freely within the cell, mtDNA can be delivered into the extracellular compartment via either extrusion of entire nucleoids or the generation and release of extracellular vesicles. Once discarded, mtDNA may act as a damage-associated molecular pattern (DAMP) and trigger an innate immune inflammatory response by binding to danger-signal receptors. Neuroinflammation is associated with a large array of neurological disorders for which mitochondrial DAMPs could represent a common thread supporting disease progression. The exploration of non-canonical pathways involved in mitochondrial quality control and neurodegeneration may unveil novel targets for the development of therapeutic agents. Here, we discuss these processes in the setting of two common neurodegenerative diseases (Alzheimer’s and Parkinson’s disease) and Down syndrome, the most frequent progeroid syndrome.

中文翻译：

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线粒体功能障碍，氧化应激和神经炎症：神经变性的交错之路。

氧化应激反应是对损伤的反应，反映出细胞抗氧化能力的破坏。因此，微调活性氧（ROS）的生成对于保持细胞的动态平衡至关重要。线粒体是ROS的主要来源和直接靶标。在不同的刺激下，包括氧化应激和质量控制受损，线粒体成分（例如，线粒体DNA，mtDNA）向细胞内或细胞外区室转移。但是，负责mtDNA卸载的机制仍不清楚。在细胞内自由穿梭的同时，mtDNA可以通过整个核苷酸的挤出或细胞外小泡的产生和释放而被递送到细胞外隔室。一旦丢弃，mtDNA可能充当损伤相关分子模式（DAMP），并通过与危险信号受体结合而触发先天性免疫炎症反应。神经炎症与大量神经系统疾病有关，线粒体DAMPs可能代表着支持疾病进展的共同线索。线粒体质量控制和神经变性涉及的非经典途径的探索可能会揭示治疗剂开发的新目标。在这里，我们将讨论两种常见的神经退行性疾病（阿尔茨海默氏病和帕金森氏病）和唐氏综合症（最常见的早老综合症）的发病过程。神经炎症与大量神经系统疾病有关，线粒体DAMPs可能代表着支持疾病进展的共同线索。线粒体质量控制和神经变性涉及的非经典途径的探索可能会揭示治疗剂开发的新目标。在这里，我们将讨论两种常见的神经退行性疾病（阿尔茨海默氏病和帕金森氏病）和唐氏综合症（最常见的早老综合症）的发病过程。神经炎症与大量神经系统疾病有关，线粒体DAMPs可能代表着支持疾病进展的共同线索。线粒体质量控制和神经变性涉及的非经典途径的探索可能会揭示治疗剂开发的新目标。在这里，我们将讨论两种常见的神经退行性疾病（阿尔茨海默氏病和帕金森氏病）和唐氏综合症（最常见的早老综合症）的发病过程。