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Mitochondrial Ca²⁺ influx plays a critical role in celastrol-induced paraptotic cell death

Authors
Lee, AReum; Yoon, Mi Jin; Choi, Kyeong Sook
Department
Department of Endocrinology & Metabolism
Abstract
Paraptosis is a cell death mode characterized by extensive vacuolization due to dilation of mitochondria and the endoplasmic reticulum (ER). However, the regulatory mechanisms that control paraptotic events, particularly the dilation of mitochondria and the ER, are not yet fully understood. We found that celastrol, a triterpene extracted from the Chinese “Thunder of God Vine” induces paraptosis accompanied by dilation of mitochondria and the ER in MDA-MB 435S and MCF-7 breast cancer cells. Celastrol increased the reactive oxygen species and ER stress resulting from the accumulation of poly-ubiquitinated proteins. Since both mitochondria and the ER are major reservoirs for intracellular Ca²⁺, we investigated the role of Ca²⁺ in paraptosis. Treatment of MDA-MB 435S cells with celastrol very rapidly increased the mitochondrial Ca²⁺ levels and the inhibition of mitochondrial Ca²⁺ uniporter employing either ruthenium red (RR) or Ru360 very potently inhibited celastrol-induced dilation of mitochondria/ER and subsequent cell death. In addition, inhibition of IP₃ receptor employing 2-aminoethoxydiphenyl borate (2-APB), but not inhibition of ryanodine receptor employing dantrolene, very effectively blocked celastrol-induced paraptotic events. Taken together, our results suggest that the release of Ca²⁺ influx into the mitochondria via uniporter critically contribute to celastrol-induced paraptosis.
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