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S. Gottipati, T. Yorio, P.R. Cammarata; Mechanism of Estrogen–mediated Cytoprotection Against Oxidative Insult: Increased Sequestration of Mitochondrial Calcium . Invest. Ophthalmol. Vis. Sci. 2005;46(13):3864.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Multiple defense mechanisms assemble at a point of regulation of mitochondrial control to provide a mitochondrial defense state which puts forward antioxidative cytoprotection against acute oxidative stress. These diverse systems involve a complex convergence of genomic and non–genomic associations; including, but not limited to, 17ß–estradiol (17ß–E2)–induced activation of signal transduction survival pathways and regulation of mitochondrial calcium homeostasis so as to prevent opening of the mitochondrial permeability transition pore. Herein we illustrate how 17ß–E2 is cytoprotective against oxidative insult which triggers excessive sustained increase in intracellular calcium ([Ca2+]i). Methods: HLE–B3 cells were grown on 25mm cover slips and the cells preincubated with 17ß–E2 (1 µM) or vehicle for 24 hrs prior to the bolus addition of 300 µM H2O2 and intracellular calcium movement monitored by Fura–2 imaging (n=70 cells per treatment). Results: 17ß–E2 pretreatment of HLE–B3 cells lessened the peroxide–induced sustained [Ca2+]i in spite of the fact that the hormone initially potentiates the influx of Ca2+ induced by peroxide.17ß–E2–induced attenuation of [Ca2+]i is mediated through the increased uptake and accumulation of Ca2+ into mitochondria. Similar results with 17α–E2 indicate that the regulation of mitochondrial Ca2+ transport is an estrogen receptor–independent function. Mitochondrial sequestration of Ca2+ is blocked by the administration of antimycin, which nullifies mitochondrial membrane potential, thus preventing mitochondrial Ca2+ transport. Conclusions: The 17ß–E2–induced attenuation of peroxide–induced sustained [Ca2+]i puts forward a novel mechanism which confers cellular protection against oxidative stress through a process of increased mitochondrial sequestration of cytosolic Ca2+. Estradiols exert their protective effects (against oxidative stress), at least in part, by stimulating mitochondrial Ca2+ transport and adjusting, to a higher–level set point, mitochondrial tolerance for Ca2+ load, thereby preventing apoptotic and/or necrotic forms of cell death that are associated with mitochondrial dysfunction otherwise initiated by disproportionate Ca2+ overload. These data establish a new mechanistic role for antioxidants and identifies novel approaches for targeting mitochondrial function to reduce oxidative stress.
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