The effect of mitochondrial transport and function on synaptic integrity during ageing

线粒体是产生ATP的小的膜结合细胞器（Kann & Kovacs, 2007）。ATP对神经元功能至关重要（Cai & Sheng, 2011），包括突触囊泡的填充、释放和再循环（Takeda & Ueda, 2017）以及钙稳态的维持（Werth & Thayer, 1994）。有效的线粒体运输和适当的线粒体分布对于确保线粒体能够服务于神经元的所有部分，特别是高度依赖能量的区域，如突触至关重要（Cai & sheng, 2011）。此外，线粒体功能和运输对于其他货物的运输很重要，因为细胞内运输依赖于atp （Zala et al., 2013）。Vagnoni实验室发现，线粒体运输随着年龄的增长而减少（Vagnoni等人，2016），他们使用了一种新的方法，通过对翅膀内的感觉神经元轴突进行成像，对活果蝇的货物运输进行成像（Vagnoni & Bullock, 2016）。此外，该实验室表明，通过实验提高衰老果蝇神经元中线粒体运输水平（通过刺激camp / PKA通路）具有保护作用，降低氧化应激水平（Vagnoni & Bullock, 2018）。该实验室有初步证据表明，淀粉样蛋白前体蛋白（APP）也由运动蛋白马达运输，随着年龄的增长，其运输量减少。然而，目前尚不清楚这是否与线粒体运输缺陷有关。突触是突触前神经元和突触后细胞（通常是另一个神经元）之间的连接（Sudhof, 2018）。突触对于神经传递至关重要——神经递质在突触中的扩散以及随后被突触后细胞表面的受体检测（Sudhof, 2018）。细胞粘附分子neurexin（在突触前细胞膜上）和neuroigin（在突触后细胞膜上）将突触前和突触后细胞连接在一起，使它们对突触的形成和维持尤为重要（Craig & Kang, 2007）。研究表明，神经素和神经素通过微管网络和动力蛋白/动力蛋白运动蛋白像线粒体一样在神经元中运输（Kneussel, 2011; Puthanveettil et al., 2008）。事实上，激酶1的敲低会阻止神经素向突触移动，导致其在体细胞和轴突初始段积累（Neupert等，2015）。研究表明，突触功能障碍发生在衰老过程中（Morrison & Baxter, 2012），是几种神经退行性疾病的标志（Wishart et al., 2006）。神经素和神经素已被证明与阿尔茨海默病中存在的淀粉样蛋白相互作用，表明突触在阿尔茨海默病的发病机制中发挥功能作用（Brito-Moreira等人，2017）。总之，线粒体对突触健康很重要。有证据表明，线粒体运输功能障碍和突触功能障碍都与衰老有关。然而，还有一些未知因素。没有研究明确表明，在衰老过程中，有缺陷的线粒体运输如何影响突触稳定性，或其他货物（如神经素和神经素）的运输。此外，我们不知道线粒体运输缺陷如何影响衰老过程中与神经退行性疾病相关的蛋白质（如APP）的运输。这些问题很重要，因为它们将使我们更好地了解导致突触功能与年龄相关的衰退的因素，突触功能是大脑功能障碍的一个常见特征。

Mitochondria are small membrane-bound organelles that generate ATP(Kann & Kovacs, 2007). ATP is essential for neuronalfunction(Cai & Sheng, 2011), including the filling, release, and recycling of synaptic vesicles (Takeda & Ueda, 2017) and the maintenance of calcium homeostasis (Werth & Thayer, 1994). Efficient mitochondrial transport and proper mitochondrial distribution is critical to ensure mitochondria can service all parts of the neuron, especially highly energy-dependent regions such as the synapses (Cai & sheng, 2011). Furthermore, mitochondrial function and transport is important for the trafficking of other cargo, as intracellular transport is ATP-dependent (Zala et al., 2013).The Vagnoni lab found that mitochondrial transport decreases with ageing (Vagnoni et al., 2016), using a novel method to image cargo transport in live Drosophila by imaging the sensory neuron axons within the wing (Vagnoni & Bullock, 2016). Furthermore, the lab showed that experimentally elevating levels of mitochondrial transport in aged Drosophila neurons (by stimulating thecAMP/ PKA pathway) has a protective effect, reducing oxidative stress levels (Vagnoni & Bullock, 2018). The lab has preliminary evidence that amyloid precursors protein (APP), which is also transported by the kinesin motor, shows decreased trafficking during ageing. However, it is not clear whether this is linked to the defective mitochondrial transport effect. Synapses are junctions between a presynaptic neuron and a postsynaptic cell, usually another neuron (Sudhof, 2018). Synapses are essential for neurotransmission -the diffusion of neurotransmitters across the synapse and their subsequent detection by receptors on the postsynaptic cell surface (Sudhof, 2018). Cell adhesion molecules neurexin (on the presynaptic cell membrane) and neuroligin (on the postsynaptic cell membrane) tether the pre-and post-synaptic cells together, making them particularly important for synapse formation and maintenance (Craig & Kang, 2007). Studies have shown that neurexin and neuroligin are transported through neurons much like mitochondria, using the microtubule network and kinesin/ dynein motor proteins (Kneussel, 2011; Puthanveettil et al., 2008). Indeed, knockdown of kinesin-1 stops neurexin moving towards synapses, causing it to accumulate at the soma and axon initial segment (Neupert et al., 2015). Studies have shown that synaptic dysfunction occurs during ageing (Morrison & Baxter, 2012) and is a hallmark of several neurodegenerative diseases (Wishart et al., 2006). Neuroligin and neurexin have been shown to interact with amyloidogenic proteins, present in Alzheimer's disease, indicating an functional role for synapses in Alzheimer's pathogenesis (Brito-Moreira et al., 2017). In conclusion, it is clear mitochondria are important for synaptic health. The evidence shows that both mitochondrial transport dysfunction and synaptic dysfunction are associated with ageing. However, there are several unknowns. No study has unequivocally shown how defective mitochondrial transport affects synaptic stability, or the transport of other cargo like neurexin and neuroligin, during ageing. Furthermore, we do not know how defective mitochondrial transport affects the trafficking of neurodegenerative disease-relevant proteins like APP during ageing. These questions are important as they would enable us to better understand the factors causing age-related decline in synapse function, a common feature of brain dysfunction.