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Xiaohua Gong, Audrey Kim, Lucy Li, Chun-hong Xia; Metabolomics of wild-type and Gja3 connexin mutant lenses in mice. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2474. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
To characterize the metabolic profiles of wild-type (WT) and Gja3 knockout (KO) mouse lenses in various genetic backgrounds including C57BL/6J and 129S4 (or 129SvJae). To test a hypothesis that gap junction channels selectively transport native metabolites to maintain lens homeostasis and that mice of different strain backgrounds display significant variation in lens homeostasis.
To characterize the metabolic profiles of lenses from postnatal day 21 (P21) WT and KO mice in different strain backgrounds by Mass-spec analysis. Profiles between KO and WT were analyzed by Random Forest (RF) analysis that attempted to bin individual samples in groups based on their metabolite similarities and differences.
The present data set comprises a total of 435 compounds of known identity (named biochemicals). The most abundant and important antioxidant is glutathione. Gja3 KO resulted in low lens glutathione levels. Reduced glutathione (GSH) was decreased in the KO lenses of all strains, compared to WT. Oxidized glutathione was relatively unchanged between KOs and WTs across all strains. Anaerobic glycolysis is reported to be the principle energy generation pathway utilized in the lens. Gja3 KO resulted in alterations of glycolysis pathway intermediates. Glucose levels either increased or decreased in KO lenses of various mouse strain backgrounds. Sugar alcohols, such as sorbitol levels represented by an isobar of mannitol and sorbitol, remained relatively constant despite varying glucose levels between KOs and WTs.
Comparison of metabolite profiles between Gja3 KO and WT lenses revealed differences of a large number of metabolites. In addition, lens metabolite profiles varied between B6 and 129 strains. Levels of antioxidants were clearly affected by Gja3 knockout. Glutathione was reduced in KO lenses from all stains, but other antioxidants, such as taurine, showed obvious strain-dependent differences. Energy metabolism, represented by the glycolysis pathway intermediates, was clearly altered in KO lenses when compared to WT lenses, suggesting that glycolysis may be impaired in Gja3 KO lenses. Knockout of Gja3 resulted in altered metabolism in the mouse eye lens and metabolite differences may provide novel insights for examining the roles of Gja3 in lens homeostasis and cataract formation.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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