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D.A. Fox, L. He, G.A. Perkins, A.T. Poblenz, M.H. Ellisman, J.B. Harris; Bcl-xL Overexpression Blocks Translocation of Cytosolic Bax to Rod Mitochondria and Rod-selective Apoptosis in Developmentally Lead-exposed Mice . Invest. Ophthalmol. Vis. Sci. 2003;44(13):2831.
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Purpose: Low-level developmental lead exposure produces persistent rod ERG alterations in children and rodents as well as slow progressive rod-selective apoptosis in rats and mice. This study used wild-type and transgenic mice overexpressing the anti-apoptotic protein Bcl-xL in photoreceptors to examine the potential role of the pro-apoptotic proteins Bax and Bid in lead-induced rod apoptosis. Methods: Newborn mice were raised by dams drinking water (controls) or 0.15% lead acetate solution. At weaning (postnatal day 21), we studied rod mitochondrial structure using three-dimensional electron microscopic tomography; examined cytochrome c release, Bax translocation and Bid cleavage using immunoblots; assayed for retinal caspase-3 and caspase-8 activity; and measured rod Ca2+ content in all four treatment groups: control, Bcl-xL, Lead and Bcl-xL/Lead. Results: Lead-induced rod-selective apoptosis was accompanied by Ca2+ overload, translocation of cytosolic Bax to the mitochondria, mitochondrial cytochrome c release, caspase-3 activation and an increase in the number of mitochondrial contact sites. These effects occurred without mitochondrial swelling, cristae topography or connectivity alterations, or outer membrane rupture; caspase-8 activation; and Bid cleavage. Bcl-xL overexpression completely blocked all apoptotic events, except Ca2+ overload, and maintained normal rod mitochondrial function. Conclusions: These results show that Bcl-xL overexpression blocked the increase in contact sites, activation of the cytochrome c/caspase-3 cascade, and rod apoptosis by inhibiting Bax translocation and suggest that mitochondrial Bax sensitized the Ca2+ overloaded rod mitochondria in lead-exposed mice to release cytochrome c. These findings reveal the complexities of the apoptotic signaling pathway and identify several different potential therapeutic target sites for humans and animals with retinal degeneration due to lead exposure, Ca2+ overload and mitochondrial dysfunction.
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