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H.Z. Malina, B.E. Frueh; New mechanism of eye diseases development: xanthurenic acid driven caspase induction and cytoskeleton polymerisation . Invest. Ophthalmol. Vis. Sci. 2004;45(13):4672.
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Purpose: Xanthurenic acid is formed by the enzymatic deamination of 3–hydroxykynure–nine, a product of tryptophan degradation by IDO. Xanthurenic acid accumulates in cells with aging and leads to covalent modification of proteins. The cell death occurs by changing of proteins conformation. We have previously published that xanthurenic acid induced caspase–9 and caspase–3. The caspase–9 activation occurs by cytochrome c release. Here, we are looking for the upstream events leading to cytochrome c release and the lack of cytoskeleton disintegration. Methods: Primary lens epithelial cells, retinal epithelial cells and retinal astrocytes were isolated from the post–mortem eye (woman 38 years) harvested for cornea transplantation. The control cells and the cells in the presence of 5 and 10 micromoles xanthurenic acid were cultivated for 96 h. Western blot analysis, immunoprecipitation, and confocal microscopy were used in the studies. Results: In the cells growing in the presence of 10 mM xanthurenic acid (intracellular 0.2 mM) the proapoptotic proteins from the Bcl–2 family (Bax, Bad) were translocated into mitochondria and cytochrome c was released. 14–3–3 proteins were translocated into lysosomes. Bax liberated from binding with 14–3–3 binds to calmodulin (CAM). Bax–CAM conjugate was translocated into mitochondria leading to cytochrome c release. We observed the post–apoptotic anarchic elongation of cytoskeleton and tubes formation from post–apoptotic aggregates. It suggests that this mechanism is also involved in vasculogenesis. Conclusions: An interruption of the physiological network of proteins occurs in the presence of xanthurenic acid accumulated in the cells. Xanthurenic acid is an endogenous crosslinker of proteins. The new interactions between proteins are formed leading to the eye diseases development with aging.
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