May 2003
Volume 44, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2003
Differential Regulation of the Mitochondrial Permeability Transition Pore in Retinal Ganglion Cells
Author Affiliations & Notes
  • J.P. Vrabec
    Ophthalmology and Visual Sciences, Univ of Wisconsin-Madison, Madison, WI, United States
  • C.J. Lieven
    Ophthalmology and Visual Sciences, Univ of Wisconsin-Madison, Madison, WI, United States
  • L.A. Levin
    Ophthalmology and Visual Sciences, Univ of Wisconsin-Madison, Madison, WI, United States
  • Footnotes
    Commercial Relationships  J.P. Vrabec, None; C.J. Lieven, None; L.A. Levin, None.
  • Footnotes
    Support  NIH Grant EY12492
Investigative Ophthalmology & Visual Science May 2003, Vol.44, 5232. doi:
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      J.P. Vrabec, C.J. Lieven, L.A. Levin; Differential Regulation of the Mitochondrial Permeability Transition Pore in Retinal Ganglion Cells . Invest. Ophthalmol. Vis. Sci. 2003;44(13):5232.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Abstract: : Purpose: To study the role of the mitochondrial permeability transition pore (PTP) in retinal ganglion cell apoptosis after axotomy. Methods: RGCs were retrogradely labeled with DiI by stereotactic injection into the superior colliculi of anesthetized postnatal day 3 Long Evans rats. 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 using the dual-emission probe JC-1, and correlated with the results of the viability experiments. 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, significantly greater than the cell death from PK11195 alone (p < 0.01). RGC death was not prevented by either caspase inhibition, or by inhibition of multiple reactive oxygen species pathways. Toxicity was also independent of the calcineurin activity of CsA and the non-specific benzodiazepine receptor activity of PK11195. Real-time imaging of RGC Δψm revealed mitochondrial depolarization after treatment with the combination of CsA and PK11195, but not with either drug alone, suggesting aberrant regulation of the PTP in these cells (p =0.012). In addition, the treatment resulted in distinct changes in mitochondrial morphology, characterized by the formation of ring-like bodies, and similar to that seen with the potassium ionophore valinomycin. Similar findings were not seen with other retinal neurons or neuronally differentiated PC-12 cells. Conclusions: The paradoxical effects of standard agents known to modulate mitochondrial PTP 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. We hypothesize that unique RGC PTP behavior could underlie the pathophysiology of those mitochondrial diseases where RGCs are specifically affected. CR: None Support: NIH EY12492

Keywords: apoptosis/cell death • ganglion cells • mitochondria 
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