Cock, Hannah Rutherford; (1997) Molecular mechanisms in mitochondrial diseases. Doctoral thesis (M.D), UCL (University College London).

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Abstract

Despite the characterization of human mitochondrial DNA (mtDNA), many of the molecular mechanisms involved in the pathogenesis of mitochondrial diseases, in particular the role of nuclear genes, are poorly understood. Cultured cells from families with Leber's hereditary optic neuropathy (LHON), and from subjects with Hutchinson-Gilford progeria syndrome (HGPS), a clinical model of accelerated ageing, were studied. Complex I activity was not decreased in 11,778 LHON lymphoblasts, or in 14,484 LHON fibroblasts, but a severe defect was confirmed in 3,460 LHON fibroblasts. However further characterization of the 3,460 fibroblasts demonstrated normal ATP synthesis in the presence of complex I linked substrates. This was not due to abnormal rotenone binding, inadequate sensitivity of the ATP assay, or a threshold effect. Analysis of specific complex I subunits, and mitochondrial protein synthesis in 3,460 fibroblasts were qualitatively normal. Fusion of enucleated 3,460 fibroblasts with P0 cells was able to restore complex I enzyme activities to control levels, supporting a role for nuclear genes in the biochemical expression of this mutation. However the functional inconsistencies between the different mtDNA mutations, and the failure to distinguish clinically affected from unaffected individuals further complicates the debate on the role of mitochondrial dysfunction in the pathogenesis of LHON. A decline in mitochondrial function with donor ageing was confirmed in cultured fibroblasts from healthy controls. All cell cultures had low levels of mtDNA bearing the "common" deletion. Fibroblasts from two subjects with HGPS exhibited significant defects in complexes II/III and IV, which were not observed in fusion cybrids generated from enucleated HGPS fibroblasts and P0 cells. Studies on mtDNA and mitochondrially synthesized proteins in HGPS did not detect any qualitative abnormalities. It is proposed that mitochondrial dysfunction, secondary to a nuclear defect, may play a role in the pathogenesis of HGPS. This could have bearing on the findings in biological ageing.

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