Investigating the pathogenesis of mitochondrial dysfunction in mitochondrial and other myopathies

Abstract

Skeletal muscle contains a large number of mitochondria, known for their production of ATP via oxidative phosphorylation, which is of vital importance for energy-demanding muscle contraction. However, the mitochondria also have a plethora of other functions such as; calcium ion homeostasis, iron-sulphur cluster formation, redox signalling and apoptotic signalling, which are of similarly high importance to skeletal muscle function. As such, it is of little surprise that mitochondrial dysfunction has been linked to a large number of neuromuscular conditions as well as healthy skeletal muscle ageing and sarcopenia. However, the mechanisms by which the dysfunction occurs and its pathological and clinical relevance remains to be understood. This thesis therefore aims to advance the understanding of mechanisms and pathological significance of mitochondrial dysfunction in mitochondrial disease, myofibrillar myopathy, dysferlin myopathy and skeletal muscle ageing. The project was approached from three very different angles. Firstly, by exploring mitochondrial dysfunction in myofibrillar myopathy, dysferlinopathy and looking for potential links to disease pathology. Secondly, by attempting to understand mechanisms and factors effecting clonal expansion of mitochondrial DNA (mtDNA) mutations, which accumulate with age in post mitotic tissues in both healthy individuals and those affected by neuromuscular and neurodegenerative disorders. Both of these approaches were investigated using histochemical, immunocytochemical and single cell genetic methodologies. Finally, possible links between mitochondrial morphology, ultrastructure and function were investigated using electron microscopy techniques. This work provides novel insights into mitochondrial involvement in neuromuscular disease pathology. Key findings include; the reduction of mitochondrial mass in myofibrillar myopathy, increased respiratory chain deficiency in some patients with dysferlinopathy, the spectrum of mitochondrial ultrastructural defects in mitochondrial myopathy, the anisotropic nature of the skeletal muscle mitochondria, the perinuclear origins of mtDNA deletions and their clonal expansion due to retrograde signalling and mitochondrial biogenesis.