Megakoniyal Konjenital Müsküler Distrofi Hastalığında Mitokondri Dinamiğinin İncelenmesi

Abstract

Mitochondrial fusion and fission events, important constituents of mitochondrial quality control mechanisms, are known as mitochondrial dynamics and regulate morphology and function of the organelle. Although mitochondrial dysfunction and dysmorphology have been implicated in the pathogenesis of several different neuromuscular disorders, no studies to date have investigated the potential role of mitochondrial dynamics in the progression of these disorders. In this thesis, the potential role of mitochondrial dynamics in the pathogenesis of Megaconial Congenital Muscular Dystrophy (CMD) has been investigated. Megaconial CMD is characterized by enlarged (megaconial) mitochondria at the periphery of muscle fibers and caused by mutations in the Choline Kinase Beta (CHKB) gene which encodes an enzyme that catalyzes the first step of phosphatidylcholine biosynthesis. In this study, after differentiation of primary myoblasts of Megaconial CMD patient into myotubes, impaired mitochondrial dynamics, localization and morphology were observed by immunofluorescent (IF) staining. Proteins involved in mitochondrial fusion and fission were analyzed by Western Blot and IF analysis. A statistically significant decrease in the expression levels of fission proteins (Drp1, Mff, Fis1) were detected compared to control [as 3.6 (***p<0.0001), 2.1 (***p<0.0001), and 3 fold (**p<0.0025) respectively], but there was no statistically significant difference in the expression levels of fusion proteins (Mfn1, Mfn2, OPA1). Moreover, the results of in-vitro studies were confirmed in skeletal muscle biopsy of a Megaconial CMD patient.