Pan JA, Fan Y, Gandhirajan RK, Madesh M, Zong WX

Intracellular calcium overload plays a critical role in numerous pathological syndromes such as heart failure, brain ischemia and stroke. Hyperactivation of the acid-sensing ion channels including degenerin/epithelial amiloride-sensitive sodium (DEG/ENaC) channels has been shown to elevate intracellular calcium and cause subsequent neuronal cell death that is independent of the canonical ...

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Egl-1/Ced-9/Ced-4/Ced-3 apoptotic pathway in C. elegans. In mammalian cells, hyperactivation of the DEG/ENaC channels can also lead to cell death, though the underlying mechanism remains largely unknown. Here, we use a tetracycline inducible system to express the hyperactivation mutant of a mammalian DEG/ENaC channel protein, MDEG G430F, in murine kidney epithelial cells deficient in the key mitochondrial apoptotic proteins Bax and Bak. Remarkably, expression of MDEG G430F induces increased intracellular calcium, ROS production, and cell death. The MDEG G430F-induced cell death is blocked by the intracellular calcium chelator BAPTA-AM, ROS scavengers, and the caspase inhibitor z-VAD-fmk. Mechanistically, the intracellular calcium overload and ROS increase lead to the inhibition of proteasomal and autophagic protein degradation, which promotes the accumulation of protein aggregates containing caspase-8 and subsequent caspase-8 activation. As protein aggregation upon the inhibition of proteasomal and autophagic degradation pathways is mediated by the ubiquitin binding protein SQSTM1/p62 and the autophagy-related protein LC3, silencing of p62 and LC3 protects cells from MDEG G430F-induced cell death. Our results uncover a new mechanism of caspase-8-mediated apoptosis induced by intracellular calcium overload that is dependent on the autophagy-related proteins LC3 and p62 upon hyperactivation of DEG/ENaC channels.

Date: Dec. 13, 2012

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