Partial loss of MCU mitigates pathology in vivo across a diverse range of neurodegenerative disease models.
Partial loss of MCU mitigates pathology in vivo across a diverse range of neurodegenerative disease models.
复制标题
MCU 的部分缺失可减轻多种神经退行性疾病模型的体内病理学。
DOI：
10.1016/j.celrep.2024.113681
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发表时间：
2024
期刊：
影响因子：
8.8
通讯作者：
Twyning MJ
中科院分区：
文献类型：
--
作者：
Twyning MJ
线粒体钙（Ca 2+）摄取增强代谢过程并缓冲胞质Ca 2+水平;然而，过量的线粒体Ca 2+可导致细胞死亡。线粒体功能和Ca 2+稳态的破坏与许多神经退行性疾病（ND）有关，但线粒体Ca 2+破坏的影响尚未得到很好的理解。在这里，我们发现，多种ND（帕金森氏症，亨廷顿氏症，阿尔茨海默氏症，额颞叶痴呆症）的果蝇模型揭示了神经元线粒体Ca 2+水平的一致增加，以及线粒体Ca 2+缓冲能力的降低，与增加的海马-内质网接触位点（MERC）相关。重要的是，线粒体Ca 2+摄取通道MCU的缺失或外排通道NCLX的过表达强烈抑制了这些ND模型中的关键病理表型。因此，线粒体Ca 2+失衡是多种ND在体内的共同特征，并且是疾病发病机制的重要贡献者。在这些模型中，MCU部分丧失的广泛有益效果为治疗干预提供了一个共同的可药物化目标。
Mitochondrial calcium (Ca2+) uptake augments metabolic processes and buffers cytosolic Ca2+levels; however, excessive mitochondrial Ca2+can cause cell death. Disrupted mitochondrial function and Ca2+homeostasis are linked to numerous neurodegenerative diseases (NDs), but the impact of mitochondrial Ca2+disruption is not well understood. Here, we show thatDrosophilamodels of multiple NDs (Parkinson's, Huntington's, Alzheimer's, and frontotemporal dementia) reveal a consistent increase in neuronal mitochondrial Ca2+levels, as well as reduced mitochondrial Ca2+buffering capacity, associated with increased mitochondria-endoplasmic reticulum contact sites (MERCs). Importantly, loss of the mitochondrial Ca2+uptake channel MCU or overexpression of the efflux channel NCLX robustly suppresses key pathological phenotypes across these ND models. Thus, mitochondrial Ca2+imbalance is a common feature of diverse NDsin vivoand is an important contributor to the disease pathogenesis. The broad beneficial effects from partial loss of MCU across these models presents a common, druggable target for therapeutic intervention.