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Joshua P. Vrabec, Christopher J. Lieven, Leonard A. Levin; Cell-Type-Specific Opening of the Retinal Ganglion Cell Mitochondrial Permeability Transition Pore. Invest. Ophthalmol. Vis. Sci. 2003;44(6):2774-2782. doi: 10.1167/iovs.02-1061.
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purpose. To study the role of the mitochondrial permeability transition pore (PTP) in apoptosis of axotomized retinal ganglion cells (RGCs) in vitro.
methods. Primary rat retinal cultures containing DiI-labeled RGCs were treated with pharmacological agents that modulate the PTP. Ratiometric imaging of the mitochondrial membrane potential (ΔΨm) were conducted on similarly treated cultures, with the dual-emission probe JC-1, and the correlation with the results of the viability experiments were determined.
results. The peripheral benzodiazepine receptor agonist PK11195 induced RGC death, but this was not inhibited by cyclosporin A (CsA), which normally maintains the PTP in the closed configuration. Paradoxically, the combination of CsA and PK11195 caused massive RGC death and decreased ΔΨm, suggesting aberrant regulation of the PTP in these cells. Imaging of ΔΨm revealed morphologic changes in the mitochondria after depolarization, characterized by formation of ringlike bodies, and similar to that with the potassium ionophore valinomycin. There were no such findings with other retinal neurons or neuronally differentiated PC-12 cells. The anomalous RGC death was independent of caspase activation or reactive oxygen species production.
conclusions. These results suggest an aberrant opening of the RGC PTP and could be the result of structural differences in its components or its interaction with intracellular ligands. Unique RGC PTP behavior could underlie the pathophysiology of those mitochondrial diseases in which RGCs are specifically affected (e.g., Leber hereditary optic neuropathy).
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