engleski

Nitric oxide synthase expression and activity in cell models relevant to human pathophysiology

Due to complex interactions of mitochondrial and nuclear DNA, the real cause of inherited mitochondrial diseases is still unclear and patients currently lack effective treatments. Leber’s hereditary optic neuropathy (LHON), one of the most common inherited optic neuropathies, is caused by point mutations in mtDNA that result in a defect of respiratory chain complex I activity. From the biochemical point of view the bioenergetic failure and the enhanced reactive oxygen species (ROS) production are typical hallmarks of LHON disease, but still they do not explain the late onset and the incomplete penetrance. Moreover it is still unknown why, although the mutation is present overall the body only the RGCs are affected. Since LHON is characterized by a deficit in the oxidative phosphorylation chain and NO· is an established mitochondrial respiratory chain negative modulator, we checked if it might have a role in the LHON development and progression. The results presented in this thesis prove that long–term exposure to NO· has a larger impact on LHON cells viability compared to controls and suggest that higher levels of reactive oxygen and nitrogen species (ONOO- ) are produced in this pathological state, leading to cell death. In addition, careful though still statistically insufficient evaluations of the levels of iNOS and eNOS mRNA expression seems to suggest that there might be a difference in the expression of one or more NOSs in LHON patients: this question however remains open. Future perspectives are, indeed, to provide a complete picture about involvement of NO· in this specific mitochondrial disease and to solve the conundrum of the NOSs expression and activity. . The feeling is that the NO· metabolism can be relevant to LHON pathophysiology, its comprehension opening to the development of more efficient therapeutic and preventive interventions.

Leber’s hereditary optic neuropathy ; nitric oxide

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