We demonstrate that a loss of NCLX decreases mtCa2+ extrusion in CRC cells and that this increase in mtCa2+ has important consequences on colorectal tumor cells: NCLX loss (1) inhibits proliferation and primary tumor growth, while (2) enhances metastasis, and drug resistance, suggesting that a loss of NCLX contributes to CRC metastatic progression. Here, SLC8B1 is linked to colorectal carcinoma.