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Mausumi Bandyopadhyay, Cecile Nasarre, Nathan Perron, Christopher Lindsey, Richard Comer, Craig Beeson, Baerbel Rohrer; An oxo-indolinone that targets mitochondria reduces photoreceptor cell loss in models of retinitis pigmentosa (RP). Invest. Ophthalmol. Vis. Sci. 2014;55(13):1912.
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Mitochondria generate the majority of a cell’s energy and integrate life and death decisions. The process of fission/fusion, biogenesis and mitophagy is critical to maintain mitochondrial integrity and thereby cellular health. We have hypothesized that loss of mitochondrial homeostasis underlies degenerative pathologies. Previously, we screened for molecules that prevent loss of mitochondrial homeostasis during metabolic stress to protect against cell loss. Here we examined the effects of one of the compounds, 1-butyl-3-hydroxy-3-(2-oxo-2-(pyridin-2-yl) ethyl) indolin-2-one (termed CB11), in models of RP.
Effects of CB11 were tested for efficacy in reducing cell loss in vitro (661w cells treated with calcium ionophore A23187), in situ (organ cultures of genetic RP models) and in vivo (constant light damage in Balb/c mice). Cell loss was quantified using MTT assays or cell counts. Cytotoxicity was determined by dose-escalation. The effects on mitochondrial capacity were assessed using Seahorse respirometry. Quantitative RT-PCR was performed to assess potential mechanisms of action for CB11. Finally, biodistribution of CB11 was determined in pig eyes after topical administration, using HPLC.
CB11 increased survival and mitochondrial function in 661w cells challenged with A23187 or IBMX, respectively, but had no cytotoxic effects in two cell lines. Photoreceptor loss in RPE-retina explants derived from rd1 mouse or S334ter rat pups was significantly attenuated when treated with CB11 in the culture media. Similarly, daily eyedrops with CB11 reduced photoreceptor cell loss in Balb/c mice exposed to constant light as shown in cell counts and protein content for rhodopsin. In these retinas, mRNA levels for genes involved in mitochondrial dynamics were found to be elevated. Finally, CB11 accumulated in the pig retina at physiologically relevant concentrations 2 hours after eye drop application.
Hence, irrespective of the trigger for degeneration (environmental or genetic mutations), CB11 reduced photoreceptor cell loss. Since CB11 increased mitochondrial respiratory capacity and expression for genes involved in mitochondrial dynamics, we suggest that CB11 targets mitochondria. Improvement of mitochondrial integrity and capacity allows for maintenance of cellular homeostasis and thereby extends the life span of cells.
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