MCU controls melanoma progression through a redox‐controlled phenotype switch

Melanoma is the deadliest of skin cancers and has a high tendency to metastasize to distant organs. Calcium and metabolic signals contribute to melanoma invasiveness; however, the underlying molecular details are elusive. The MCU complex is a major route for calcium into the mitochondrial matrix but whether MCU affects melanoma pathobiology was not understood. Here, we show that MCU(A) expression correlates with melanoma patient survival and is decreased in BRAF kinase inhibitor‐resistant melanomas. Knockdown (KD) of MCU(A) suppresses melanoma cell growth and stimulates migration and invasion. In melanoma xenografts, MCU(A_KD) reduces tumor volumes but promotes lung metastases. Proteomic analyses and protein microarrays identify pathways that link MCU(A) and melanoma cell phenotype and suggest a major role for redox regulation. Antioxidants enhance melanoma cell migration, while prooxidants diminish the MCU(A_KD)‐induced invasive phenotype. Furthermore, MCU(A_KD) increases melanoma cell resistance to immunotherapies and ferroptosis. Collectively, we demonstrate that MCU(A) controls melanoma aggressive behavior and therapeutic sensitivity. Manipulations of mitochondrial calcium and redox homeostasis, in combination with current therapies, should be considered in treating advanced melanoma.