MCU controls melanoma progression through a redox‐controlled phenotype switch

Abstract

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 MCUA expression correlates with melanoma patient survival and is decreased in BRAF kinase inhibitor‐resistant melanomas. Knockdown (KD) of MCUA suppresses melanoma cell growth and stimulates migration and invasion. In melanoma xenografts, MCUA_KD reduces tumor volumes but promotes lung metastases. Proteomic analyses and protein microarrays identify pathways that link MCUA and melanoma cell phenotype and suggest a major role for redox regulation. Antioxidants enhance melanoma cell migration, while prooxidants diminish the MCUA_KD‐induced invasive phenotype. Furthermore, MCUA_KD increases melanoma cell resistance to immunotherapies and ferroptosis. Collectively, we demonstrate that MCUA 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.

Synopsis

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The MCU channel complex is the main route for Ca2+ into the mitochondrial matrix. MCU controls cellular redox state, disease aggressiveness and therapeutic response and is a favorable prognostic marker in melanoma.

MCU controls mitochondrial Ca2+ dynamics, production of ROS and ATP in melanoma cells. MCU downregulation hinders melanoma cell growth and stimulates cellular motility and metastasis. Melanoma cells develop increased resistance to immunotherapies and ferroptosis inducers upon MCU downregulation.

The MCU channel complex is the main route for Ca2+ into the mitochondrial matrix. MCU controls cellular redox state, disease aggressiveness and therapeutic response and is a favorable prognostic marker in melanoma. image