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Editors Selection IGR 16-1

Basic Research: Abnormal mitochondrial function and GON

Comment by Robert Casson on:

45733 A selective inhibitor of Drp1, Mdivi-1, increases retinal ganglion cell survival in acute ischemic mouse retina, Park SW; Kim K-Y; Lindsey JD et al., Investigative Ophthalmology and Visual Science, 2011; 52: 2837-2843

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This paper builds on a recent body of work with interesting hypotheses and well-conducted experiments. Motivated by the notion that abnormal mitochondrial function may be a pathogenic component of glaucomatous optic neuropathy (GON), Park et al. (916) hypothesized that elevated intraocular pressure (IOP) may affect mitochondrial fission and fusion (fission can initiate apoptosis). In a previous study on RGC-5 cells, they showed that elevated hydrostatic pressure (in the absence of any gas tension changes) caused translocation of the mitochondrial fission-inducing protein, dynamin-related protein 1 (Drp-1) from the cytosol to the mitochondria with ultrastructural changes and subsequent apoptotic cell death. (Ju et al. IOVS 2007; 48; 2145‐2151). An earlier in-vivo study showed that ten-month-old DBA/2J mice with IOPs > 20 mmHg had ultrastructural mitochondrial changes and increased Dnm1 expression (a rat homologue of Drp-1). (Ju et al. IOVS 2008; 49: 4903-4911) They concluded that pressure-induced mitochondrial dysfunction may contribute to retinal ganglion cell (RGC) death and GON. The current study aimed to determine whether acute IOP elevation (above perfusion pressure) alters Drp1, and whether a selective inhibitor of Drp1, mdivi-1, can block apoptotic cell death and increase RGC survival in ischemic mouse retina. They use well-documented techniques to show that intraperitoneal mdivi-1 attenuates retinal apoptosis, RGC loss, and macroglial reaction in this ischaemic model. Mdivi-1 did not alter expression of Drp1, and the authors devote little discussion to this observation; however, this is not unexpected because mdivi-1 may affect assembly of the protein, but not necessarily epitope expression captured by the antibody used. The only unconvincing data is the immunostaining of Drp-1 localization in the retina. A positive control would have been valuable. The Western blotting is more convincing, but inclusion of molecular weights in the figures would have been beneficial. Mdivi-1 appears to be another experimental ischaemic retina neuroprotectant, added to a long list. Presumably, the researchers felt that their DBA/2J model was not appropriate for this experiment. However, a rat glaucoma model would perhaps have been more relevant. It is difficult to see the translational opportunities. Uncoupling pressure-induced injury from an ischemic/hypoxic injury is challenging in any current model. However, further investigation of the effect of pressure on mitochondria in another model (not RGC-5) would be an interesting experiment, potentially linking the mechanical and energy-insufficiency theories of GON.

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