 Abstract | This PhD study aimed to characterise the pathophysiology of a novel mitochondrial mutation in a patient with a mitochondrial myopathy. This mutation, an adenine insertion at nucleotide (nt) position 3230 of the human mitochondrial genome (RefSeq NC_012920), was shown to significantly disrupt transcription termination, leading to increases in the levels of both the genome-length mitochondrial DNA (mtDNA) polycistronic transcript and selected mRNAs encoding subunits of the respiratory chain complexes. A corresponding increase in the levels of two subunits of Cytochrome c oxidase (COX, Complex IV) was observed; however, there was no increase in the levels of any of the respiratory chain holocomplexes. Complex I and Complex IV activities were elevated in the proband's tissues. No evidence of DNA damage through apoptosis or necrosis was found and the proband's cells did not show elevated levels of 8-hydroxy-2-deoxyguanosine, a biomarker of oxidative stress. Attenuation of transcription termination in human mitochondria appears to be a novel mechanism of mitochondrial disease. |
