Induction of Paraptosis by Cyclometalated Iridium Complex-Peptide Hybrids and CGP37157 via a Mitochondrial Ca2+ Overload Triggered by Membrane Fusion between Mitochondria and the Endoplasmic Reticulum

We previously reported that a cyclometalated iridium (Ir) complex-peptide hybrid (IPH) 4 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 (CA²⁺) from the endoplasmic reticulum (ER) to mitochondria. Here, we describe that CGP37157, an inhibitor of a mitochondrial sodium (Na⁺)/CA²⁺ exchanger, induces Paraptosis in Jurkat cells via intracellular pathways similar to those induced by 4. The findings allow us to suggest that the induction of Paraptosis by 4 and CGP37157 is associated with membrane fusion between mitochondria and the ER, subsequent CA²⁺ influx from the ER to mitochondria, and a decrease in the mitochondrial membrane potential (ΔΨ_m). 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 4 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).