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Editors Selection IGR 14-4
Basic Research: Role of OPA-1 in apoptosis
Comment by Larry Wheeler on:
22927 Glutamate receptor activation triggers OPA1 release and induces apoptotic cell death in ischemic rat retina, Ju W-K; Lindsey JD; Angert M et al., Molecular Vision, 2008; 14: 2629-2638
Two recent papers by Ju et al. have provided a link between NMDA receptor activation, release of the mitochondrial protein OPA-1 to cytosol, and apoptosis of retinal neurons in acute and chronic pressure models. OPA-1 plays a major role in mitochondrial fusion. In healthy cells, mitochrondria are dynamic organelles that continuously undergo fisson and fusion. Disruption of this balance can contribute to neural injury. Dysregulation of OPA-1 results in mitochondrial dysfunction that leads to release of cytochrome c that triggers apoptosis. Interestingly, mutations in OPA-1 have been linked with neurodegenerative diseases such as autosomal dominant optic atrophy. In the first study by Ju et al. (91) the investigators show in an acute rat retinal ischemia model, that long and short forms of OPA1 are released into the cytosol of ischemic retinas and that MK801 blocks OPA1 release as well as ischemia induced apoptosis. Ischemia has been shown to cause an elevation of extracellular glutamate level that is likely to cause an overactivation of NMDA receptors in the retina.
It is suggested that in high IOP-induced RGC/retinal injury, particularly in the glaucoma model, the NMDA receptor plays a central role in mitochondrial dysfunction and RGC deathThus, the new results provide a link between NMDA receptor overactivation that results in release of mitochondrial OPA-1 into the cytosol as a step neuronal apoptosis. In the second paper by Ju et al. (92) they demonstrate with the ocular hypertensive DBA/2J mouse model that a more chronic elevation of IOP can also cause OPA1 release into the cytosol and this release is blocked by memantine. Memantine treatment almost fully protected RGCs showing that NMDA receptor overactivation is a major cause of RGC death. This paper adds new downstream information about how OPA1 dysregulation can play a role in a chronic glaucoma model. In addition to normalizing OPA1, NMDA receptor blockade also prevented mitochondrial dysfunction by increasing Bcl-2 and decreasing Bax gene expression.
Taken together, these studies suggest in high IOP-induced RGC/retinal injury, particularly in the glaucoma model, that the NMDA receptor plays a central role in mitochondrial dysfunction and RGC death. The authors also commented about the results of the Memantine Trial (J Pharm Exp Ther 2001; 296: 216). The authors' data in animal models show good efficacy of memantine. Perhaps animal models do not predict human efficacy? Was the memantine started early enough in the clinical trial? Were the doses and clinical endpoints chosen, the right ones to show neuroprotection? Only more clinical work will answer these types of questions. In summary, these new studies provide evidence that OPA-1 regulation as an important downstream target that emphasizes the role of the mitochrondria in NMDA receptor mediated excitotoxicity in the retina/optic nerve.
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