A novel mechanism for the pyruvate protection against zincinduced cytotoxicity: mediation by the chelating effect of citrate and isocitrate

다국어 초록 (Multilingual Abstract)

Intracellular accumulation of free zinc contributesto neuronal death in brain injuries such as ischemiaand epilepsy. Pyruvate, a glucose metabolite, has beenshown to block zinc neurotoxicity. However, it is largelyunknown how pyruvate shows such a selective andremarkable protective effect. In this study, we sought tofind a plausible mechanism of pyruvate protection againstzinc toxicity. Pyruvate almost completely blocked corticalneuronal death induced by zinc, yet showed no protectiveeffects against death induced by calcium (ionomycin,NMDA) or ferrous iron. Of the TCA cycle intermediates,citrate, isocitrate, and to a lesser extent oxaloacetate, protectedagainst zinc toxicity. We then noted with LC–MS/MS assay that exposure to pyruvate, and to a lesser degreeoxaloacetate, increased levels of citrate and isocitrate,which are known zinc chelators. While pyruvate addedonly during zinc exposure did not reduce zinc toxicity,citrate and isocitrate added only during zinc exposure, asdid extracellular zinc chelator CaEDTA, completelyblocked it. Furthermore, addition of pyruvate after zincexposure substantially reduced intracellular zinc levels.
Our results suggest that the remarkable protective effect ofpyruvate against zinc cytotoxicity may be mediated indirectlyby the accumulation of intracellular citrate andisocitrate, which act as intracellular zinc chelators.

참고문헌 (Reference)

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