Involvement of mitochondria in SELENON-Related Myopathy


Translational Research

Poster Number: M250


Pamela Barraza, PhD, Boston Children's Hospital / Harvard Medical School, Behzad Moghadaszadeh, PhD, Boston Children's Hospital, Won Lee, Boston Children's Hospital, Biju Isaac, PhD, Boston Children's Hospital, Ashish Jain, PhD, Boston Children's Hospital, Liang Sun, PhD, Boston Children's Hospital, Emily Hickey, Boston Children's Hospital / Harvard Medical School, Shira Rockowitz, PhD, Boston Children's Hospital, Alan Beggs, PhD, Boston Children's Hospital / Harvard Medical School

SELENON-Related Myopathy (SELENON-RM) is caused by recessive mutations of the SELENON gene. It is characterized by axial muscle weakness with progressive respiratory insufficiency. The most common histopathological features in muscle biopsies are multiminicores, which are areas of mitochondria depletion. There are currently no effective treatments for SELENON-RM. The SELENON gene encodes selenoprotein N (SelN), a redox enzyme located at the endoplasmic reticulum membrane. Additionally, SelN has been shown to colocalize with mitochondria-associated membranes (MAMs). However, the molecular mechanism(s) by which SelN deficiency causes SELENON-RM is undetermined. 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. To demonstrate this, we mechanically challenged our zebrafish model for SELENON-RM and report changes in glutathione redox homeostasis as well as enlarged muscle mitochondria when compared to WT. Additionally, we report abnormalities of glycolytic and cellular respiration in myotubes from SelN deficient mice. 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.