Dichotomous role of the human mitochondrial Na/Ca2/Li exchanger NCLX in colorectal cancer growth and metastasis.

Despite the established role of mitochondria in cancer, the mechanisms by which mitochondrial Ca (mtCa) regulates tumorigenesis remain incompletely understood. The crucial role of mtCa in tumorigenesis is highlighted by altered expression of proteins mediating mtCa uptake and extrusion in cancer. Here, we demonstrate decreased expression of the mitochondrial Na/Ca/Li exchanger NCLX () in human colorectal tumors and its association with advanced-stage disease in patients. Downregulation of NCLX causes mtCa 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, mtCa 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 mtCa is a novel therapeutic approach in metastatic colorectal cancer.