Purchase this article with an account.
Patrick Yu-Wai-Man, Kamil S. Sitarz, Joanna D. Stewart, Angela Pyle, Bernd Rautenstrauss, Pavel Seeman, Rita Horvath, Patrick F. Chinnery; Mitofusin 2 (MFN2) Mutations Cause Mitochondrial DNA Instability In Charcot-Marie-Tooth Disease. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1310. doi: https://doi.org/.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of inherited peripheral neuropathies and it affects at least 1 in 2,500 individuals. A specific autosomal-dominant axonal CMT subtype, hereditary motor and sensory neuropathy type VI (HMSN-VI, OMIM 601152), is caused by mutations in mitofusin 2 (MFN2, 1p36.2). In addition to early-onset severe peripheral neuropathy, affected individuals also develop progressive optic nerve dysfunction in later childhood. MFN2 is a critical mitochondrial outer membrane protein and it shares a remarkable degree of structural and functional complementarity with OPA1, a mitochondrial inner membrane protein implicated in the majority of cases of autosomal-dominant optic atrophy (ADOA, OMIM 165500). The aim of this study was to provide new mechanistic insights by investigating the deleterious influence of MFN2 mutations on mitochondrial biogenesis.
Tissue samples were available from 48 patients with confirmed MFN2 mutations. Using well-established molecular protocols, various markers of mitochondrial dysfunction were assayed including: (i) mitochondrial DNA (mtDNA) proliferation in blood leukocytes, (ii) the presence of biochemically-defective cytochrome c oxidase (COX) fibers in skeletal muscle biopsies, and (iii) the kinetics of mtDNA repopulation in fibroblast cultures after ethidium bromide-induced depletion.
Blood leukocytes from MFN2-positive patients had significantly increased mtDNA copy numbers (Mean = 205.9, n = 48) compared with age-matched controls (Mean = 60.9, n = 131; p < 0.0001). Significant mtDNA proliferation was also evident in skeletal muscle fibers from MFN2-positive patients. COX-negative skeletal muscle fibers were present and these harboured high levels of somatic mtDNA deletions, accounting for the observed respiratory chain defect. MFN2-positive fibroblasts had significantly impaired rates of mtDNA repopulation following a period of increased cellular stress.
The MFN2 protein is intricately involved in mtDNA maintenance and the faithful replication of the mitochondrial genome. Pathogenic MFN2 mutations ultimately lead to neuronal cell loss by triggering a mitochondrial biochemical defect.
This PDF is available to Subscribers Only