Department of Integrative Biology, University of Wisconsin, Madison, United States.
Department of Neuroscience, University of Wisconsin, Madison, United States.
Elife. 2021 Mar 24;10:e59687. doi: 10.7554/eLife.59687.
Endoplasmic reticulum (ER) and mitochondria form close physical associations to facilitate calcium transfer, thereby regulating mitochondrial function. Neurons with high metabolic demands, such as sensory hair cells, are especially dependent on precisely regulated ER-mitochondria associations. We previously showed that the secreted metalloprotease pregnancy-associated plasma protein-aa (Pappaa) regulates mitochondrial function in zebrafish lateral line hair cells (Alassaf et al., 2019). Here, we show that mutant hair cells exhibit excessive and abnormally close ER-mitochondria associations, suggesting increased ER-mitochondria calcium transfer. mutant hair cells are more vulnerable to pharmacological induction of ER-calcium transfer. Additionally, mutant hair cells display ER stress and dysfunctional downstream processes of the ER-mitochondria axis including altered mitochondrial morphology and reduced autophagy. We further show that Pappaa influences ER-calcium transfer and autophagy via its ability to stimulate insulin-like growth factor-1 bioavailability. Together our results identify Pappaa as a novel regulator of the ER-mitochondria axis.
内质网（ER）和线粒体形成紧密的物理联系，以促进钙转移，从而调节线粒体功能。代谢需求高的神经元，如感觉毛细胞，特别依赖于精确调节的 ER-线粒体联系。我们之前表明，分泌的金属蛋白酶妊娠相关血浆蛋白-aa（Pappaa）调节斑马鱼侧线毛细胞中的线粒体功能（Alassaf 等人，2019 年）。在这里，我们表明 突变体毛细胞表现出过度和异常紧密的 ER-线粒体联系，表明 ER-线粒体钙转移增加。 突变体毛细胞对 ER 钙转移的药理学诱导更敏感。此外， 突变体毛细胞表现出 ER 应激和 ER-线粒体轴的功能障碍下游过程，包括改变线粒体形态和减少自噬。我们进一步表明，Pappaa 通过刺激胰岛素样生长因子-1 的生物利用度来影响 ER-钙转移和自噬。总之，我们的结果表明 Pappaa 是 ER-线粒体轴的一个新的调节剂。
