Oxidative stress and other proapoptotic factors can lead to mitochondrial damage and result in the opening of the mitochondrial permeability transition pore (MPTP). This allows for the leakage of cytochrome c, which activates procaspace-9 and triggers apoptotic death pathways. Retinal ganglion cells and their axons in the optic nerve may undergo such pathophysiology in diseases, such as hereditary optic neuropathies and glaucoma.
In the present study, a mouse model of glaucoma was used and preglaucomatous mice received memantine while their IOP was regularly measured. After sacrifice, the retinas of the mice were studied by immunohistochemistry, Western blot and TUNEL staining to assess the presence of OPA1 protein, apoptosis and a few other factors.
The authors found that memantine mitigated release of OPA1 from mitochondria and this was mediated through the blockade by memantine of glutamate receptors. This memantine-induced effect was accompanied by decreased Bax gene expression and increased Bcl-2 gene expression. These genes help regulate the opening and closing of the MPTP as pro- and anti-apoptotic factors, respectively.
OPA1 is one member of a family of dynamin-related proteins that together with the mitofusins allow mitochondria to fuse. This is part of a dynamic balance of fusion and fission crucial to mitochondrial health and function. Mutations of OPA1 have been shown to be associated with autosomal dominant optic atrophy (ADOA). In the absence of OPA1, there is likely a relative ascendancy of mitochondrial fission. This is probably associated with cytochrome c release and apoptosis, which, at least in the case of ADOA, leads to optic atrophy.
This study, therefore, has several important implications including the following:
- Glaucoma probably involves the glutamate intercellular signaling system.
- These receptors prompt intracellular signals that promote the release of OPA1 from mitochondria.
- Lack of OPA1 may direct the mitochondria to remain in predominant fission form, and this leads to mitochondrial injury.
- This mitochondrial stress causes MPTP opening, which involves Bcl-2 and Bax gene expression, and the probable release of cytochrome c.
- This leads to apoptosis of retinal ganglion cells, which causes the optic atrophy associated with glaucoma.
- Memantine can block glutamate receptors and possibly preclude this damage to the optic nerve if applied prophylactically.
This study also reminds us of the central role of mitochondria, not only as organelles that produce stored energy in the form of ATP, but as linchpins in the process of neuronal apoptosis. This last point is now being confirmed in a variety of other optic neuropathies, including Leber hereditary optic neuropathy, toxic and nutritional optic neuropathies and other more general neurological diseases.
Dr. Sadun is a consultant to Allergan, Inc., and Pfizer Ophthalmics.