Hypometabolism tied to mitochondrial dysfunction occurs in the aging brain and in neurodegenerative disorders, including in Alzheimer’s disease, in Down syndrome, and in mouse models of these conditions. We have previously shown that mitovesicles, small extracellular vesicles (EVs) of mitochondrial origin, are altered in content and abundance in multiple brain conditions characterized by mitochondrial dysfunction. However, given their recent discovery, it is yet to be explored what mitovesicles regulate and modify, both under physiological conditions and in the diseased brain. In this study, we investigated the effects of mitovesicles on synaptic function, and the molecular players involved. Hippocampal slices from wild-type mice were perfused with the three known types of EVs, mitovesicles, microvesicles, or exosomes, isolated from the brain of a mouse model of Down syndrome or of a diploid control and long-term potentiation (LTP) recorded. The role of the monoamine oxidases type B (MAO-B) and type A (MAO-A) in mitovesicle-driven LTP impairments was addressed by treatment of mitovesicles with the irreversible MAO inhibitors pargyline and clorgiline prior to perfusion of the hippocampal slices. Mitovesicles from the brain of the Down syndrome model reduced LTP within minutes of mitovesicle addition. Mitovesicles isolated from control brains did not trigger electrophysiological effects, nor did other types of brain EVs (microvesicles and exosomes) from any genotype tested. Depleting mitovesicles of their MAO-B, but not MAO-A, activity eliminated their ability to alter LTP. Mitovesicle impairment of LTP is a previously undescribed paracrine-like mechanism by which EVs modulate synaptic activity, demonstrating that mitovesicles are active participants in the propagation of cellular and functional homeostatic changes in the context of neurodegenerative disorders.

中文翻译：

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线粒体功能障碍的大脑细胞外空间分泌的线粒体会损害突触可塑性


与线粒体功能障碍相关的代谢减退发生在衰老的大脑和神经退行性疾病中，包括阿尔茨海默病、唐氏综合症以及这些疾病的小鼠模型。我们之前已经证明，在以线粒体功能障碍为特征的多种脑部疾病中，线粒体起源的小细胞外囊泡（EV）的含量和丰度发生了改变。然而，鉴于他们最近的发现，尚待探索在生理条件下和患病大脑中线粒体小泡的调节和改变。在这项研究中，我们研究了线粒体小泡对突触功能的影响以及所涉及的分子参与者。野生型小鼠的海马切片灌注了三种已知类型的 EV、线粒体、微泡或外泌体，这些细胞是从唐氏综合症小鼠模型或二倍体对照小鼠模型的大脑中分离出来的，并记录了长时程增强 (LTP)。 B 型单胺氧化酶 (MAO-B) 和 A 型单胺氧化酶 (MAO-A) 在线粒体驱动的 LTP 损伤中的作用通过在灌注海马切片之前用不可逆 MAO 抑制剂帕吉兰和氯吉兰处理线粒体来解决。来自唐氏综合症模型大脑的线粒体在添加线粒体后几分钟内就降低了 LTP。从对照大脑中分离出的线粒体不会引发电生理效应，来自任何测试基因型的其他类型的大脑 EV（微泡和外泌体）也不会引发电生理效应。耗尽其 MAO-B（而非 MAO-A）活性的线粒体就消除了它们改变 LTP 的能力。 LTP 的线粒体小泡损伤是一种先前未描述的类旁分泌机制，EV 通过该机制调节突触活动，表明线粒体小泡是神经退行性疾病背景下细胞和功能稳态变化传播的积极参与者。