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Abstract：
Selenoprotein N (SEPN1) is a type II glycoprotein of the endoplasmic reticulum (ER) that senses calcium levels to tune the activity of the sarcoplasmic reticulum calcium pump (SERCA pump) through a redox-mediated mechanism, modulating ER calcium homeostasis. In SEPN1-depleted muscles, altered ER calcium homeostasis triggers ER stress, which induces CHOP-mediated malfunction, altering excitation-contraction coupling. SEPN1 is localized in a region of the ER where the latter is in close contact with mitochondria, i.e., the mitochondria-associated membranes (MAM), which are important for calcium mobilization from the ER to mitochondria. Accordingly, SEPN1-depleted models have impairment of both ER and mitochondria calcium regulation and ATP production. SEPN1-related myopathy (SEPN1-RM) is an inherited congenital muscle disease due to SEPN1 loss of function, whose main histopathological features are minicores, i.e., areas of mitochondria depletion and sarcomere disorganization in muscle fibers. SEPN1-RM presents with weakness involving predominantly axial and diaphragmatic muscles. Since there is currently no disease-modifying drug to treat this myopathy, analysis of SEPN1 function in parallel with that of the muscle phenotype in SEPN1 loss of function models should help in understanding the pathogenic basis of the disease and possibly point to novel drugs for therapy. The present essay recapitulates the novel biological findings on SEPN1 and how these reconcile with the muscle and bioenergetics phenotype of SEPN1-related myopathy.
摘要：
硒蛋白N（SEPN1）是内质网（ER）的II型糖蛋白，可通过氧化还原介导的机制感知钙水平以调节肌浆网钙泵（SERCA泵）的活性，调节ER钙稳态。在SEPN1耗尽的肌肉中，改变ER钙稳态引发ER应激，诱导CHOP介导的功能障碍，改变激励-收缩耦合。SEPN1位于ER的一个区域，后者与线粒体紧密接触，即，线粒体相关膜（MAM），这对于钙从内质网动员到线粒体是重要的。因此，SEPN1耗尽模型对ER和线粒体钙调节和ATP产生均有损害。SEPN1相关肌病（SEPN1-RM）是一种遗传性先天性肌肉疾病，由于SEPN1功能丧失，其主要组织病理学特征是微小细胞，即，肌肉纤维中线粒体耗竭和肌节解体的区域。SEPN1-RM表现出主要涉及轴向和膈肌的无力。由于目前还没有治疗这种肌病的改善疾病的药物，同时分析SEPN1功能缺失模型中的SEPN1功能和肌肉表型应有助于了解疾病的致病基础,并可能指向用于治疗的新药物.本文概述了SEPN1的新生物学发现，以及这些发现如何与SEPN1相关肌病的肌肉和生物能学表型相协调。
