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Photoreceptor apoptosis and resultant visual deficits occur in humans and animals with inherited and disease-, injury-, and chemical-induced retinal degeneration. A clinically relevant mouse photoreceptors. A multiparametric analysis of rod apoptosis and mitochondrial structure-function was performed. Mitochondrial cristae topography and connectivity, matrix volume, and contact sites were examined by using 3D electron tomography. Lead-induced rod-selective apoptosis was accompanied by rod [Ca.sup.2+] overload, rhodopsin loss, translocation of Bax from the cytosol to the mitochondria, decreased rod mitochondrial respiration and membrane potential, mitochondrial cytochrome c release, caspase-3 activation, and an increase in the number of mitochondrial contact sites. These effects occurred without mitochondrial matrix swelling, outer membrane rupture, caspase-8 activation, or Bid cleavage. Bcl-[x.sub.L] overexpression completely blocked all apoptotic events, except [Ca.sup.2+] overload, and maintained normal rod mitochondrial function throughout adulthood. This study presents images of mitochondrial contact sites in an in vivo apoptosis model and shows that Bcl-[x.sub.L] overexpression blocks increased contact sites and apoptosis. These findings extend our in vitro retinal studies with [Pb.sup.2+] and [Ca.sup.2+] and suggest that developmental lead exposure produced rod-selective apoptosis without mitochondrial swelling by translocating cytosolic Bax to the mitochondria, which likely sensitized the [Pb.sup.2+] and [Ca.sup.2+] overloaded rod mitochondria to release cytochrome c. These results have relevance for therapies in where [Ca.sup.2+] overload, lead exposure, and/or mitochondrial dysfunction occur.

Photoreceptor apoptosis and resultant visual deficits occur in humans and animals with inherited and disease-, injury-, and chemical-induced retinal degeneration. A clinically relevant mouse model of progressive rod photoreceptor-selecfive apoptosis was produced by Iow-level developmental lead exposure and studied in combination with transgenic mice overexpressing Bcl-x[sub L] only in the photoreceptors. A multiparametric analysis of rod apoptosis and mitochondrial structure-function was performed. Mitochondrial cristae topography and connectivity, matrix volume, and contact sites were examined by using 3D electron tomography. Leadinduced rod-selective apoptosis was accompanied by rod Ca[sup 2+] overload, rhodopsin loss, translocation of Bax from the cytosol to the mitochondria, decreased rod mitochondrial respiration and membrane potential, mitochondrial cytochrome c release, caspase-3 activation, and an increase in the number of mitochondrial contact sites. These effects occurred without mitochondriai matrix swelling, outer membrane rupture, caspase-8 activation, or Bid cleavage. BCI-X[sub L] overexpression completely blocked all apoptotic events, except Ca[sup 2+] overload, and maintained normal rod mitochondrial function throughout adulthood. This study presents images of mitochondriai contact sites in an in vivo apoptosis model and shows that Bcl-x[sub L] overexpression blocks increased contact sites and apoptosis. These findings extend our in vitro retinal studies with Pb[sup 2+] and Ca[sup 2+] and suggest that developmental lead exposure produced rod-selective apoptosis without mitochondrial swelling by translocating cytosolic Bax to the mitochondria, which likely sensitized the Pb[sup 2+] and Ca[sup 2+] overloaded rod mitochondria to release cytochrome c. These results have relevance for therapies in a wide variety of progressive retinal and neuronal degenerations where Ca[sup 2+] overload, lead exposure, and/or mitochondrial dysfunction occur. [ABSTRACT FROM AUTHOR]