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Abstract Mitochondrial Ca 2+ uptake shapes cellular signaling by modulating metabolism, cell death and cytosolic Ca 2+ dynamics, yet its pathological and therapeutic relevance remains undefined. Here, we show that Ca 2+ entry through the mitochondrial Ca 2+ uniporter (MCU) is required for mitochondrial fragmentation and subsequent NLRP3 inflammasome-mediated IL-1β release in lipopolysaccharide-primed, stimulated macrophages. This fragmentation occurs independently of the mitochondrial permeability transition pore but depends on activation of the organelle fission machinery. In an inflammatory disease model, MCU deficiency attenuated IL-1β secretion and reduced monosodium urate (MSU) crystal-induced joint inflammation in vivo. Collectively, our findings establish mitochondrial Ca 2+ uptake as a key upstream signal that promotes organelle fragmentation to license inflammasome activation, positioning MCU as a potential therapeutic target in inflammatory diseases.
Gherardi et al. (Wed,) studied this question.