Mitochondrial dysfunction in hereditary optic neuropathies

摘要: MITOCHONDRIAL DYSFUNCTION IN HEREDITARY OPTIC NEUROPATHIES Mitochondrial pathologies are a heterogeneous group of clinical manifestations characterized by oxidative phosphorylation impairment. At the beginning their recognition mitochondrial were regarded as rare disorders but indeed they more frequent than originally thought. Due to unique mitochondria peculiarities can be caused mutations in both and nuclear genomes. The poor knowledge pathologic mechanism these has not allowed real development “mitochondrial medicine”, that is currently limited symptoms mitigation. Leber hereditary optic neuropathy (LHON) was first pathology linked point mutation mtDNA. which gene encoding Complex I subunits leads nerve degeneration still unknown, although well accepted other genetic or environmental factors involved modulation pathology, where pivotal role certainly played stress. We studied relationship between Ala16Val dimorphism targeting sequence SOD2 3460/ND1 LHON mutation. Our results show that, control population, heterozygous genotype associated higher activity quantity MnSOD, particularly with respect Val homozygotes. Furthermore, we demonstrated patients harboring at least one Ala allele an increased MnSOD relative population. Since ATP synthesis rate – severely reduced lymphocytes - affected genotype, concluded could modulate pathogenicity through increase reactive oxygen species production. Autosomal dominant atrophy (ADOA) Opa1, dynamin-related protein localized matrix. Although course slightly different, endpoint ADOA exactly same LHON: specific involvement retinal ganglion cells. Opa1 relatively new protein, whose major regulation fusion. Mitochondrial morphology equilibrium two opposite force: fusion fission, processes have finely regulated order preserve cellular physiology. fibroblasts deriving from deletion GTPase domain OPA1 gene. biochemical characterization concerned evaluation rate, membrane potential different metabolic conditions morphological status mitochondria. Regarding did find significant differences even though trend toward reduction samples observed when grown absence glucose medium containing gramicidin. found also actively maintained proton pumping fully functional respiratory chain complexes. indicate pedigree analyzed acts primary impairing without affecting energy production, supporting notion cell function tightly morphology. Mitochondrial dysfunctions acquiring great attention because recognized relevance only aging age-related including cancer, cardiovascular disease, type II diabetes, neurodegenerative disorders. such detrimental currently, become so common enhances necessity standardization therapeutic strategies capable rescuing normal function. In propose alternative treatment for deficiency-disorders tested effect substrates stimulate substrate-level on viability availability experimental models under conditions. fibroblasts, defect achieved culturing cells presence oligomycin, inhibitor synthase complex. NARP cybrids been used model pathology. Cell content considered parameters assay capability exogenous substrate rescue failure. suggest suffering some forms deficiency, deficiency might benefit dietary pharmacological based supplementation α-ketoglutarate aspartate.