Induction of Paraptosis by Cyclometalated Iridium Complex-Peptide Hybrids and CGP37157 via a Mitochondrial Ca Overload Triggered by Membrane Fusion between Mitochondria and the Endoplasmic Reticulum.

We previously reported that a cyclometalated iridium (Ir) complex-peptide hybrid (IPH) functionalized with a cationic KKKGG peptide unit on the 2-phenylpyridine ligand induces paraptosis, a relatively newly found programmed cell death, in cancer cells (Jurkat cells) via the direct transport of calcium (Ca) from the endoplasmic reticulum (ER) to mitochondria. Here, we describe that CGP37157, an inhibitor of a mitochondrial sodium (Na)/Ca exchanger, induces paraptosis in Jurkat cells via intracellular pathways similar to those induced by . The findings allow us to suggest that the induction of paraptosis by and CGP37157 is associated with membrane fusion between mitochondria and the ER, subsequent Ca influx from the ER to mitochondria, and a decrease in the mitochondrial membrane potential (). On the contrary, celastrol, a naturally occurring triterpenoid that had been reported as a paraptosis inducer in cancer cells, negligibly induces mitochondria-ER membrane fusion. Consequently, we conclude that the paraptosis induced by and CGP37157 (termed paraptosis II herein) proceeds via a signaling pathway different from that of the previously known paraptosis induced by celastrol, a process that negligibly involves membrane fusion between mitochondria and the ER (termed paraptosis I herein).