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D. A. Fox, G. A. Perkins, J. E. Johnson, A. Giddabasappa CS, S. Chaney, J. M. Brown, P. Lahsaei, S. Ghassemzadeh, A. Dixit, M. H. Ellisman; Differential Susceptibility of Rod Photoreceptor Synaptic and Non-Synaptic Mitochondria (Mt) to Postnatal Lead Exposure and Protection by Bcl-xL. Invest. Ophthalmol. Vis. Sci. 2007;48(13):2502.
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Photoreceptor apoptosis and visual deficits occur with inherited and toxicant-induced retinal degenerations, diseases and aging. Rod and cone inner segment (RIS; CIS) Mt are considered the primary target sites of action, however, rod spherule and cone pedicle Mt have not been examined.
Newborn C57BL/6 mice were raised by dams drinking water (Con) or low-level lead (Pb) solution throughout lactation. To assess spherule and RIS Mt structural and functional differences as well as sensitivity/vulnerability to postnatal Pb exposure, we used wild-type and transgenic mice that overexpressed Bcl-xL in photoreceptors (Tg). The results are compared to our RIS Mt findings (Mol Vis, 2003; PNAS, 2003). Immunocytochemistry and confocal microscopy, electron microscopy, three-dimensional electron tomography and rod synaptic terminal oxygen consumption (QO-ST) studies used adult retinas from all four groups: Con, Tg, Pb and Tg+Pb.
Molecular markers of Mt compartments revealed retinal lamination and cellular localization of Mt. Bcl-xL localized to spherule and RIS Mt. Rod spherules had one large Mt compared to ~5/RIS cross-section. Spherule Mt in Con, Tg and Tg+Pb mice were in the orthodox configuration, whereas in Pb mice they were in the aggregated configuration and swollen, had increased matrix volumes and lost a large number of cristae. The crista junction diameter of spherule Mt of Con, Tg and Tg+Pb mice were smaller than those in RISs and were further decreased in Pb mice. In contrast, Pb exposure did not alter RIS Mt matrix volume or crista junction size, although it activated an apoptotic cascade that was blocked by Bcl-xL. QO-ST in Pb mice was decreased. Bcl-xL attenuated some of the Pb-induced alterations in spherule Mt, however, persistent structural and functional alterations remained.
These results reveal compartmental specific differences in the morphology, number, substructure, sensitivity and vulnerability of rod spherule and RIS Mt to Pb, Ca2+ and likely other insults. These results provide important new data on retinal Mt injury, particularly related to divalent cation-overload, and a relevant caution for translational and therapeutic studies. They indicate that persistent structural and functional deficits, likely producing visual deficits, remain in the synaptic terminals even after rod (or cone) apoptosis is completely blocked.
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