Brooks Noah A H, Riar Ishvin, Klegeris Andis
Laboratory of Cellular and Molecular Pharmacology, Faculty of Science, University of British Columbia Okanagan Campus, Kelowna, BC, Canada.
Neural Regen Res. 2025 Jun 19. doi: 10.4103/NRR.NRR-D-24-01459.
Neuroinflammation contributes to a wide range of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. It is driven by non-neuronal glial cells, mainly microglia and astrocytes. Microglia are the resident immune cells of the central nervous system, while astrocytes are the main support cells for neuronal functions but can also participate in neuroimmune responses. Both these glial cell types can become reactive upon detection of certain endogenous intracellular molecules that appear in the extracellular space under specific circumstances; these can be pathology-associated abnormal structures, such as amyloid β proteins, or damage-associated molecular patterns released from injured cells, including their mitochondria. Once in the extracellular space, damage-associated molecular patterns act as ligands for specific pattern recognition receptors expressed by glia inducing their reactivity and neuroimmune responses. This review considers the following mitochondrial damage-associated molecular patterns: heme, cytochrome c, cardiolipin, adenosine triphosphate, mitochondrial DNA, mitochondrial transcription factor A, N-formyl peptides, and the tricarboxylic acid cycle metabolites: succinate, fumarate, and itaconate. We describe their well-established functions as damage-associated molecular patterns of the peripheral tissues before summarizing available evidence indicating these molecules may also play significant roles in the neuroimmune processes of the central nervous system. We highlight the pattern recognition receptors that mitochondrial damage-associated molecular patterns interact with and the cellular signaling mechanisms they modulate. Our review demonstrates that some mitochondrial damage-associated molecular patterns, such as cytochrome c, adenosine triphosphate, and mitochondrial transcription factor A, have already demonstrated significant effects on the central nervous system. In contrast, others including cardiolipin, mitochondrial DNA, N-formyl peptides, succinate, fumarate, and itaconate, will require additional studies corroborating their roles as damageassociated molecular patterns in the central nervous system. For all of the reviewed mitochondrial damage-associated molecular patterns, there is a shortage of studies using human cells and tissues, which is identified as a significant knowledge gap. We also assess the need for targeted research on the effects of mitochondrial damage-associated molecular patterns in the central nervous system pathologies where their roles are understudied. Such studies could identify novel treatment strategies for multiple neurodegenerative diseases, which are characterized by chronic neuroinflammation and currently lack effective therapies.
神经炎症与多种神经退行性疾病相关，包括阿尔茨海默病、帕金森病、亨廷顿病和多发性硬化症。它由非神经元胶质细胞驱动，主要是小胶质细胞和星形胶质细胞。小胶质细胞是中枢神经系统的常驻免疫细胞，而星形胶质细胞是神经元功能的主要支持细胞，但也可参与神经免疫反应。在检测到某些在特定情况下出现在细胞外空间的内源性细胞内分子时，这两种胶质细胞类型均可发生反应；这些分子可以是与病理相关的异常结构，如淀粉样β蛋白，或从受损细胞（包括其线粒体）释放的损伤相关分子模式。一旦进入细胞外空间，损伤相关分子模式就作为胶质细胞表达的特定模式识别受体的配体，诱导其反应性和神经免疫反应。本综述考虑了以下线粒体损伤相关分子模式：血红素、细胞色素c、心磷脂、三磷酸腺苷、线粒体DNA、线粒体转录因子A、N-甲酰肽以及三羧酸循环代谢产物：琥珀酸、富马酸和衣康酸。在总结现有证据表明这些分子也可能在中枢神经系统的神经免疫过程中发挥重要作用之前，我们先描述它们作为外周组织损伤相关分子模式的既定功能。我们强调线粒体损伤相关分子模式与之相互作用的模式识别受体及其调节的细胞信号机制。我们的综述表明，一些线粒体损伤相关分子模式，如细胞色素c、三磷酸腺苷和线粒体转录因子A，已对中枢神经系统产生显著影响。相比之下，其他分子，包括心磷脂、线粒体DNA、N-甲酰肽、琥珀酸、富马酸和衣康酸，则需要更多研究来证实它们作为中枢神经系统损伤相关分子模式的作用。对于所有综述的线粒体损伤相关分子模式，使用人类细胞和组织的研究都很缺乏，这被认为是一个重大的知识空白。我们还评估了针对线粒体损伤相关分子模式在其作用尚未得到充分研究的中枢神经系统疾病中的影响进行靶向研究的必要性。此类研究可能会确定多种神经退行性疾病的新治疗策略，这些疾病以慢性神经炎症为特征，目前缺乏有效的治疗方法。
