TY - JOUR TI - Dichotomous role of the human mitochondrial Na+/Ca2+/Li+ exchanger NCLX in colorectal cancer growth and metastasis AU - Pathak, Trayambak AU - Gueguinou, Maxime AU - Walter, Vonn AU - Delierneux, Celine AU - Johnson, Martin T AU - Zhang, Xuexin AU - Xin, Ping AU - Yoast, Ryan E AU - Emrich, Scott M AU - Yochum, Gregory S AU - Sekler, Israel AU - Koltun, Walter A AU - Gill, Donald L AU - Hempel, Nadine AU - Trebak, Mohamed A2 - Nelson, Mark T A2 - Aldrich, Richard W A2 - Nelson, Mark T VL - 9 PY - 2020 DA - 2020/09/11 SP - e59686 C1 - eLife 2020;9:e59686 DO - 10.7554/eLife.59686 UR - https://doi.org/10.7554/eLife.59686 AB - Despite the established role of mitochondria in cancer, the mechanisms by which mitochondrial Ca2+ (mtCa2+) regulates tumorigenesis remain incompletely understood. The crucial role of mtCa2+ in tumorigenesis is highlighted by altered expression of proteins mediating mtCa2+ uptake and extrusion in cancer. Here, we demonstrate decreased expression of the mitochondrial Na+/Ca2+/Li+ exchanger NCLX (SLC8B1) in human colorectal tumors and its association with advanced-stage disease in patients. Downregulation of NCLX causes mtCa2+ overload, mitochondrial depolarization, decreased expression of cell-cycle genes and reduced tumor size in xenograft and spontaneous colorectal cancer mouse models. Concomitantly, NCLX downregulation drives metastatic spread, chemoresistance, and expression of epithelial-to-mesenchymal, hypoxia, and stem cell pathways. Mechanistically, mtCa2+ overload leads to increased mitochondrial reactive oxygen species, which activate HIF1α signaling supporting metastasis of NCLX-null tumor cells. Thus, loss of NCLX is a novel driver of metastasis, indicating that regulation of mtCa2+ is a novel therapeutic approach in metastatic colorectal cancer. KW - calcium signaling KW - mitochondrial calcium KW - metastasis KW - Colorectal cancer KW - HIF1a JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -