线粒体功能障碍是神经炎症和神经退行性变的关键免疫检查点:聚焦 mtDAMPs。

IF 4.6 2区 医学 Q1 NEUROSCIENCES
Molecular Neurobiology Pub Date : 2025-06-01 Epub Date: 2024-08-08 DOI:10.1007/s12035-024-04412-0
Yogesh Mishra, Ashutosh Kumar, Ravinder Kumar Kaundal
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引用次数: 0

摘要

神经炎症是阿尔茨海默病、帕金森病、肌萎缩侧索硬化症、多发性硬化症和中风等老年性和急性神经退行性疾病恶化的关键因素。线粒体对神经元的健康至关重要,因为它们在能量生产、钙缓冲和氧化应激调节方面发挥着重要作用,但在新陈代谢压力、衰老或损伤的条件下,线粒体越来越容易出现功能障碍。衰老或损伤神经元的有丝分裂功能受损会导致功能障碍线粒体的积累,从而释放线粒体衍生损伤相关分子模式(mtDAMPs)。这些 mtDAMPs 可作为免疫检查点,激活模式识别受体(PRR)并触发先天性免疫信号通路。这种激活会引发神经元和脑内免疫细胞的炎症反应,释放细胞因子和趋化因子,从而损伤邻近的健康神经元并招募外周免疫细胞,进一步加剧神经炎症和神经退行性变。长期的线粒体功能障碍会延续慢性炎症状态,加剧神经元损伤,并为细胞外环境提供更多的免疫原性成分。新出现的证据强调了 mtDAMPs 在引发和维持神经炎症中的关键作用,这些分子的循环水平有可能成为疾病进展的生物标志物。本综述探讨了线粒体功能障碍导致的 mtDAMP 释放机制、它们与 PRRs 的相互作用以及随后炎症通路的激活。我们还讨论了 mtDAMP 触发的先天性免疫反应在加剧急性和慢性神经炎症和神经变性中的作用。以功能失调的线粒体和 mtDAMPs 为靶点的药理制剂是缓解神经病理状况的启动和进展的一种前景广阔的策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Mitochondrial Dysfunction is a Crucial Immune Checkpoint for Neuroinflammation and Neurodegeneration: mtDAMPs in Focus.

Mitochondrial Dysfunction is a Crucial Immune Checkpoint for Neuroinflammation and Neurodegeneration: mtDAMPs in Focus.

Neuroinflammation is a pivotal factor in the progression of both age-related and acute neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and stroke. Mitochondria, essential for neuronal health due to their roles in energy production, calcium buffering, and oxidative stress regulation, become increasingly susceptible to dysfunction under conditions of metabolic stress, aging, or injury. Impaired mitophagy in aged or injured neurons leads to the accumulation of dysfunctional mitochondria, which release mitochondrial-derived damage-associated molecular patterns (mtDAMPs). These mtDAMPs act as immune checkpoints, activating pattern recognition receptors (PRRs) and triggering innate immune signaling pathways. This activation initiates inflammatory responses in neurons and brain-resident immune cells, releasing cytokines and chemokines that damage adjacent healthy neurons and recruit peripheral immune cells, further amplifying neuroinflammation and neurodegeneration. Long-term mitochondrial dysfunction perpetuates a chronic inflammatory state, exacerbating neuronal injury and contributing additional immunogenic components to the extracellular environment. Emerging evidence highlights the critical role of mtDAMPs in initiating and sustaining neuroinflammation, with circulating levels of these molecules potentially serving as biomarkers for disease progression. This review explores the mechanisms of mtDAMP release due to mitochondrial dysfunction, their interaction with PRRs, and the subsequent activation of inflammatory pathways. We also discuss the role of mtDAMP-triggered innate immune responses in exacerbating both acute and chronic neuroinflammation and neurodegeneration. Targeting dysfunctional mitochondria and mtDAMPs with pharmacological agents presents a promising strategy for mitigating the initiation and progression of neuropathological conditions.

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来源期刊
Molecular Neurobiology
Molecular Neurobiology 医学-神经科学
CiteScore
9.00
自引率
2.00%
发文量
480
审稿时长
1 months
期刊介绍: Molecular Neurobiology is an exciting journal for neuroscientists needing to stay in close touch with progress at the forefront of molecular brain research today. It is an especially important periodical for graduate students and "postdocs," specifically designed to synthesize and critically assess research trends for all neuroscientists hoping to stay active at the cutting edge of this dramatically developing area. This journal has proven to be crucial in departmental libraries, serving as essential reading for every committed neuroscientist who is striving to keep abreast of all rapid developments in a forefront field. Most recent significant advances in experimental and clinical neuroscience have been occurring at the molecular level. Until now, there has been no journal devoted to looking closely at this fragmented literature in a critical, coherent fashion. Each submission is thoroughly analyzed by scientists and clinicians internationally renowned for their special competence in the areas treated.
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