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.
Highlights
SELENON-related myopathy, known as SEPN1-related myopathy (SEPN1-RM), designates a rare inherited myopathy, previously classified as four different disorders, caused by homozygous or compound heterozygous mutations in the SELENON, known as SEPN1, gene (OMIM#606210) which lead to SEPN1 loss of function
SEPN1 is localized at the mitochondria-associated membranes (MAM), a region where endoplasmic reticulum (ER) is in close contact with mitochondria
MAMs, supporting the concept of high Ca2+ microdomains close to the Calcium Release Unit (CRU) which lead to Ca2+ uptake by mitochondria [9,23,24]
Summary
SELENON-related myopathy, known as SEPN1-related myopathy (SEPN1-RM), designates a rare inherited myopathy, previously classified as four different disorders, caused by homozygous or compound heterozygous mutations in the SELENON, known as SEPN1, gene (OMIM#606210) which lead to SEPN1 loss of function. The thioredoxin-like domain of SEPN1, containing the highly nucleophilic selenocysteine, is possibly more exposed. This facilitates redox modulation of its partners, including the sarcoplasmic/endoplasmic reticulum calcium pump (SERCA), which is activated to pump calcium from the cytosol into the ER [4]. SEPN1 is localized at the MAMs, a region where ER is in close contact with mitochondria. It regulates calcium levels in the ER and in mitochondria, in fine tuning ATP and muscle bioenergetics [6,7]. We first describe the features of SEPN1 myopathy and briefly summarize the main features of the link between Ca2+ and redox homeostasis in the ER, to turn to the specific roles of SEPN1 in the regulation of the Ca2+ –redox link in the ER lumen and in mitochondrial Ca2+ content, OXPHOS function and ATP production
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