Mitochondrial population maintenance in neurons is essential for neuron function and survival. Contact sites between mitochondria and the endoplasmic reticulum (ER) are poised to regulate mitochondrial homeostasis in neurons. These contact sites can facilitate transfer of calcium and lipids between the organelles and have been shown to regulate aspects of mitochondrial dynamics. Vesicle-associated membrane protein-associated protein B (VapB) is an ER membrane protein present at a subset of ER–mitochondrial contact sites. A proline-to-serine mutation in VapB at amino acid 56 (P56S) correlates with susceptibility to amyotrophic lateral sclerosis (ALS) type 8. Given the relationship between failed mitochondrial health and neurodegenerative disease, we investigated the function of VapB in mitochondrial population maintenance. We demonstrated that transgenic expression of VapB^P56S in zebrafish larvae (sex undetermined) increased mitochondrial biogenesis, causing increased mitochondrial population size in the axon terminal. Expression of wild-type VapB did not alter biogenesis but, instead, increased mitophagy in the axon terminal. Using genetic manipulations to independently increase mitochondrial biogenesis, we show that biogenesis is normally balanced by mitophagy to maintain a constant mitochondrial population size. VapB^P56S transgenics fail to increase mitophagy to compensate for the increase in mitochondrial biogenesis, suggesting an impaired mitophagic response. Finally, using a synthetic ER–mitochondrial tether, we show that VapB's function in mitochondrial turnover is likely independent of ER–mitochondrial tethering by contact sites. Our findings demonstrate that VapB can control mitochondrial turnover in the axon terminal, and this function is altered by the P56S ALS-linked mutation.

神经元中线粒体群的维持对于神经元功能和存活至关重要。线粒体和内质网（ER）之间的接触位点准备调节神经元中的线粒体稳态。这些接触位点可以促进钙和脂质在细胞器之间的转移，并已被证明可以调节线粒体动力学的各个方面。囊泡相关膜蛋白相关蛋白 B (VapB) 是一种内质网膜蛋白，存在于内质网与线粒体接触位点的子集上。 VapB 氨基酸 56 (P56S) 处的脯氨酸到丝氨酸突变与 8 型肌萎缩侧索硬化症 (ALS) 的易感性相关。考虑到线粒体健康不良与神经退行性疾病之间的关系，我们研究了 VapB 在线粒体群体维持中的功能。我们证明，斑马鱼幼虫（性别未定）中 VapB ^P56S的转基因表达增加了线粒体生物发生，导致轴突末端线粒体群体大小增加。野生型 VapB 的表达并没有改变生物发生，而是增加了轴突末端的线粒体自噬。使用遗传操作独立增加线粒体生物发生，我们表明生物发生通常通过线粒体自噬来平衡，以维持恒定的线粒体群体大小。 VapB ^P56S转基因无法增加线粒体自噬来补偿线粒体生物合成的增加，表明线粒体自噬反应受损。最后，使用合成的 ER-线粒体系链，我们表明 VapB 在线粒体周转中的功能可能独立于接触位点的 ER-线粒体系链。 我们的研究结果表明，VapB 可以控制轴突末端的线粒体周转，并且该功能因 P56S ALS 相关突变而改变。