Arachidonic acid induces both Na⁺ and Ca²⁺ entry resulting in apoptosis

Abstract

Abstract Marked accumulation of arachidonic acid (AA) and intracellular Ca 2+ and Na + overloads are seen during brain ischemia. In this study, we show that, in neurons, AA induces cytosolic Na + ([Na + ] cyt ) and Ca 2+ ([Ca 2+ ] cyt ) overload via a non‐selective cation conductance (NSCC), resulting in mitochondrial [Na + ] m and [Ca 2+ ] m overload. Another two types of free fatty acids, including oleic acid and eicosapentaenoic acid, induced a smaller increase in the [Ca 2+ ] i and [Na + ] i . RU360, a selective inhibitor of the mitochondrial Ca 2+ uniporter, inhibited the AA‐induced [Ca 2+ ] m and [Na + ] m overload, but not the [Ca 2+ ] cyt and [Na + ] cyt overload. The [Na + ] m overload was also markedly inhibited by either Ca 2+ ‐free medium or CGP3715, a selective inhibitor of the mitochondrial Na + cyt ‐Ca 2+ m exchanger. Moreover, RU360, Ca 2+ ‐free medium, Na + ‐free medium, or cyclosporin A (CsA) largely prevented AA‐induced opening of the mitochondrial permeability transition pore, cytochrome c release, and caspase 3‐dependent neuronal apoptosis. Importantly, Na + ‐ionophore/Ca 2+ ‐free medium, which induced [Na + ] m overload, but not [Ca 2+ ] m overload, also caused cyclosporin A‐sensitive mitochondrial permeability transition pore opening, resulting in caspase 3‐dependent apoptosis, indicating that [Na + ] m overload per se induced apoptosis. Our results therefore suggest that AA‐induced [Na + ] m overload, acting via activation of the NSCC, is an important upstream signal in the mitochondrial‐mediated apoptotic pathway. The NSCC may therefore act as a potential neuronal death pore which is activated by AA accumulation under pathological conditions.

Keywords

Affiliated Institutions

• National Taiwan University TW
• Central Taiwan University of Science and Technology TW

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