P421 Mitochondrial involvement in SELENON-Related Myopathy

• Published in: Neuromuscular disorders : NMD Vol. 33; pp. S157 - S158
• Main Authors: Barraza, P., Moghadaszadeh, B., Lee, W., Isaac, B., Sun, L., Troiano, E., Rockowitz, S., Sliz, P., Beggs, A.
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01-10-2023
• ISSN: 0960-8966; 1873-2364
• DOI: 10.1016/j.nmd.2023.07.362

SELENON-Related Myopathy (SELENON-RM) is caused by recessive mutations of the SELENON gene and is characterized by spinal and axial muscle weakness with progressive respiratory insufficiency. The most common histopathological features in biopsies are multiminicores (areas of mitochondria depletion). There are no effective treatments for SELENON-RM. The SELENON gene encodes selenoprotein N (SelN), a reductase enzyme involved in redox reactions located at the endoplasmic reticulum membrane. SelN has been shown to colocalize with mitochondria-associated membranes (MAMs) and participate in mitochondrial function. However, the molecular mechanism(s) by which SelN deficiency causes SELENON-RM is undetermined. Our results show that week-old selenon-KO zebrafish larvae exhibit reduced swimming activity when compared to WT. Electron microscopy of these larvae revealed enlargement of muscle mitochondria. Furthermore, mechanically challenging these fish exacerbated mitochondrial enlargement. Analysis of single cell RNAseq data in a zebrafish embryo-atlas reveals coexpression between selenon and multiple genes involved in the glutathione redox pathway. These data support a hypothesis that SelN plays a role in modulating the redox environment in conjunction with glutathione redox reactions. Additionally, we report abnormalities of glycolytic and cellular respiration in myotubes from SelN deficient mice when seeded at high confluency. Finally, to further explore the role that mitochondria play in SELENON-RM we used muscle biopsies from patients and performed spatial transcriptomics. This format of study will help us identify and analyze fibers positive for multiminicores and compare them to control samples. These data will help us explore the mitochondrial involvement in patients with SELENON-RM. Together, our results enable a path toward disease mechanism discovery that encompasses different aspects of disease as well as providing a basis for therapeutic testing.