Insights Into the Link Between Mitochondrial Dynamics and Peripheral Neuropathies
AdvisorShutt, Timothy E.
AuthorAlmutawaa, Walaa Saeed
Committee MemberMains, Paul E.
Mitochondrial genes: MYH14, MFN2
CMT-2 : Charcot Marie Tooth disease
MetadataShow full item record
AbstractMitochondrial dynamics, which include fusion and fission events, determine mitochondrial morphology and reflect mitochondrial health within the cell. Mitochondrial dynamics are important for mitochondrial functions, including but not limited to, cellular respiration, energy production, and mitochondrial DNA (mtDNA) maintenance. Defects in mitochondrial fission and fusion proteins are associated with a number of neurological disorders including the peripheral neuropathy Charcot-Marie-Tooth Type II disease (CMT2). The research presented in this thesis centers around a novel fission protein, NMIIC (encoded by the MYH14 gene), and a well-characterized fusion protein, Mfn2, and how defects in these proteins affects mitochondrial dynamics and contribute to disease. In my first study, examining a CMT2 pathogenic variant in MYH14 that is associated with a peripheral neuropathy phenotype, I reported for the first time the role of NMIIC as a key player in mitochondrial fission. Characterization of this R941L variant in overexpression studies, and in patient fibroblasts indicated impairment of mitochondrial fission in these cells. Intriguingly, the distribution of mtDNA was also affected in fibroblast harbouring the R941L mutation. Collectively, these observations revealed a novel role for NMIIC in mitochondrial fission with defects linked to the pathogenicity of CMT2. In my second project, I examined the novel Q367H variant of MFN2, a regulator of mitochondrial fusion, which also has other important cellular roles. While pathogenic mutations in MFN2 are typically associated with CMT2, the Q367H variant I characterized was associated with myopathy phenotype rather than a peripheral neuropathy. Although commonly assumed that the peripheral neuropathy phenotype associated with MFN2 mutations is due to impaired mitochondrial fusion, accumulating evidence supported by our new data characterizing the Q367H mutation, suggests that this may not be the case. Here, I examined the effects of the Mfn2 H367Q mutation on mitochondrial morphology, endoplasmic reticulum (ER) morphology, bioenergetics function, and lipid droplet morphology. These parameters were altered in MFN2 Q367H patient fibroblasts, suggesting that this mutation is pathogenic, and thus expanding the phenotypic presentation of phenotypes in patients with MFN2 mutations. Overall, my studies provided novel insight into the link between mitochondrial dynamics and peripheral neuropathy by expanding the list of mitochondrial dynamics genes associated with peripheral neuropathy, and by characterizing mitochondrial dysfunction caused by a novel mutation in MFN2 that is not associated with CMT2.
CitationAlmutawaa, W. S. (2020). Insights Into the Link Between Mitochondrial Dynamics and Peripheral Neuropathies (Unpublished doctoral thesis). University of Calgary, Calgary, AB.
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