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V. Carelli, M. Montopoli, E. Perli, M. Orlandi, F. N. Ross-Cisneros, A. A. Sadun, A. Ghelli, G. d'Amati, C. Giordano; Estrogens Ameliorate Mitochondrial Dysfunction in Leber Hereditary Optic Neuropathy. Invest. Ophthalmol. Vis. Sci. 2010;51(13):993.
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© ARVO (1962-2015); The Authors (2016-present)
To study the influence of estrogen on mitochondrial dysfunction associated with mtDNA mutations affecting complex I pathogenic for Leber’s hereditary optic neuropathy (LHON).
Control and LHON osteosarcoma-derived cybrids (11778/ND4, 3460/ND1 and 14484/ND6) were grown in glucose or glucose-free galactose supplemented medium. After having shown the nuclear and mitochondrial localization of estrogen receptors (ERs) in cybrids, experiments were carried out adding 100nM of 17β-estradiol (17β-E2). In a set of experiments cells were pre-incubated with the ERs antagonist ICI 182,780. ROS production, cell viability, mitochondrial membrane potential, rate of apoptosis, mitochondrial network dynamics, mitochondrial biogenesis, respiration and ATP amount were evaluated. Human retinal sections from control and LHON subjects were used to study the presence of ERβ in retinal ganglion cells (RGCs).
LHON cybrids in galactose medium showed ROS overproduction, which led to decrease of mitochondrial membrane potential, increased apoptotic rate, loss of cell viability and hyper-fragmented mitochondrial morphology as compared to control cybrids. Treatment with 17β-E2 significantly rescued these pathological features that characterized LHON cybrids and led to the activation of the antioxidant enzyme SOD2. In addition, 17β-E2 induced a general activation of mitochondrial biogenesis, as revealed by the coordinated increase in expression of nuclear and mitochondrial DNA encoded subunits of respiratory complexes as well as of the master regulators PGC1α and β, NRF1 and NRF2 and Tfam. All estrogen effects were abolished by the ERs antagonist. The ERβ were shown to localize on RGCs and their axons, in a cytoplasmic punctuate pattern, and were also seen in LHON residual RGCs.
Our results provide strong evidence that estrogens play a substantial role in modulating the metabolic defect in LHON, providing a good explanation for the male prevalence of this disorder. Furthermore, the current findings suggest that treatment with estrogen or estrogen-like molecules may represent an effective therapy for this untreatable condition.
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