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

Abstract

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 (<i>SLC8B1</i>) 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.