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Fragmented mitochondria released from microglia trigger A1 astrocytic response and propagate inflammatory neurodegeneration.
Nature Neuroscience ( IF 21.2 ) Pub Date : 2019-09-23 , DOI: 10.1038/s41593-019-0486-0
Amit U Joshi 1 , Paras S Minhas 2 , Shane A Liddelow 3, 4, 5 , Bereketeab Haileselassie 1, 6 , Katrin I Andreasson 2 , Gerald W Dorn 7 , Daria Mochly-Rosen 1
Nature Neuroscience ( IF 21.2 ) Pub Date : 2019-09-23 , DOI: 10.1038/s41593-019-0486-0
Amit U Joshi 1 , Paras S Minhas 2 , Shane A Liddelow 3, 4, 5 , Bereketeab Haileselassie 1, 6 , Katrin I Andreasson 2 , Gerald W Dorn 7 , Daria Mochly-Rosen 1
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In neurodegenerative diseases, debris of dead neurons are thought to trigger glia-mediated neuroinflammation, thus increasing neuronal death. Here we show that the expression of neurotoxic proteins associated with these diseases in microglia alone is sufficient to directly trigger death of naive neurons and to propagate neuronal death through activation of naive astrocytes to the A1 state. Injury propagation is mediated, in great part, by the release of fragmented and dysfunctional microglial mitochondria into the neuronal milieu. The amount of damaged mitochondria released from microglia relative to functional mitochondria and the consequent neuronal injury are determined by Fis1-mediated mitochondrial fragmentation within the glial cells. The propagation of the inflammatory response and neuronal cell death by extracellular dysfunctional mitochondria suggests a potential new intervention for neurodegeneration-one that inhibits mitochondrial fragmentation in microglia, thus inhibiting the release of dysfunctional mitochondria into the extracellular milieu of the brain, without affecting the release of healthy neuroprotective mitochondria.
中文翻译：
从小胶质细胞释放的碎片线粒体触发 A1 星形细胞反应并传播炎症性神经变性。
在神经退行性疾病中，死亡神经元的碎片被认为会引发神经胶质细胞介导的神经炎症，从而增加神经元死亡。在这里，我们表明，仅在小胶质细胞中与这些疾病相关的神经毒性蛋白的表达就足以直接触发幼稚神经元的死亡，并通过将幼稚星形胶质细胞激活到 A1 状态来传播神经元死亡。损伤传播在很大程度上是由碎片化和功能失调的小胶质细胞线粒体释放到神经元环境中介导的。相对于功能性线粒体，从小胶质细胞释放的受损线粒体的数量以及随之而来的神经元损伤是由神经胶质细胞内 Fis1 介导的线粒体断裂决定的。
更新日期：2019-09-23
中文翻译：
从小胶质细胞释放的碎片线粒体触发 A1 星形细胞反应并传播炎症性神经变性。
在神经退行性疾病中，死亡神经元的碎片被认为会引发神经胶质细胞介导的神经炎症，从而增加神经元死亡。在这里，我们表明，仅在小胶质细胞中与这些疾病相关的神经毒性蛋白的表达就足以直接触发幼稚神经元的死亡，并通过将幼稚星形胶质细胞激活到 A1 状态来传播神经元死亡。损伤传播在很大程度上是由碎片化和功能失调的小胶质细胞线粒体释放到神经元环境中介导的。相对于功能性线粒体，从小胶质细胞释放的受损线粒体的数量以及随之而来的神经元损伤是由神经胶质细胞内 Fis1 介导的线粒体断裂决定的。
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