Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy.
Basic and Translational Myology Laboratory, UMR8251 Université de Paris/CNRS, 75013 Paris, France.
Cells. 2021 May 6;10(5):1116. doi: 10.3390/cells10051116.
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.
硒蛋白 N（SEPN1）是内质网（ER）中的一种 II 型糖蛋白，通过氧化还原介导的机制感知钙水平，调节肌浆网钙泵（SERCA 泵）的活性，调节 ER 钙稳态。在 SEPN1 耗竭的肌肉中，改变的 ER 钙稳态会引发内质网应激，这会诱导 CHOP 介导的功能障碍，改变兴奋-收缩偶联。SEPN1 定位于 ER 的一个区域，后者与线粒体密切接触，即线粒体相关膜（MAM），这对于从 ER 向线粒体动员钙很重要。因此，SEPN1 耗竭模型存在 ER 和线粒体钙调节和 ATP 产生的损伤。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核，即肌肉纤维中线粒体耗竭和肌节紊乱的区域。SEPN1-RM 表现为主要累及轴肌和膈肌的无力。由于目前尚无治疗这种肌病的疾病修饰药物，因此分析 SEPN1 功能与 SEPN1 功能丧失模型中的肌肉表型平行，应该有助于了解疾病的发病基础，并可能指向新的治疗药物。本文综述了 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表型相协调。
