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DA Fox, GA Perkins, L He, AT Poblenz, MH Ellisman, JB Harris; Bcl-xL Inhibits Lead and Calcium-Induced Rod Apoptosis by Blocking the Increase in Mitochondrial Contact Sites . Invest. Ophthalmol. Vis. Sci. 2002;43(13):1887.
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Purpose: Photoreceptor apoptosis and visual deficits occur in man and animals with inherited and chemical-induced retinal degenerations, and retinal diseases and injuries. Rod-selective apoptosis is produced by developmental lead exposure in mice and by in vitro lead and/or calcium. The latter activates the cytochrome c-caspase cascade of apoptosis. Methods: This study used wild-type and transgenic mice overexpressing Bcl-xL in photoreceptors to examine the role of mitochondria in lead-induced rod apoptosis. Newborn mice were raised by dams drinking water (controls) or 0.15% lead acetate solution. At weaning, studies of rod mitochondria were conducted in all four groups (control, Bcl-xL, Lead, Bcl-xL/Lead) using three-dimensional electron microscopic tomography, JC-1 staining, immunoblots for cytochrome c, caspase assays and oxygen consumption. Results: There were no differences between the four treatment groups for 5 of 7 different measurements of rod mitochondrial substructures (crista widths, crista junction diameters, outer (OMM)-inner membrane widths, contact site widths, contact site diameters). In contrast to the in vitro lead and/or calcium results, no physical disruptions of the OMM or swollen mitochondrial matrices were observed. Lead-induced rod apoptosis was accompanied by calcium overload, increases in mitochondrial contact site area and density, decreases in rod mitochondrial respiration and membrane potential (depolarization), cytochrome c release and caspase activation. Bcl-xL overexpression completely blocked the lead-induced increase in contact sites and all apoptotic events, except calcium overload, and maintained normal rod respiration. Conclusion: These results suggest that Bcl-xL is located and functions at mitochondrial contact sites to block the opening of the permeability transition pore and to maintain normal rod function. These findings have relevance for pharmacological and gene therapies in human and animal retinal and neuronal degenerations where lead exposure, calcium overload and/or mitochondrial dysfunction occur.
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