Work

Mitochondrial calcium uptake drives organelle remodeling to promote inflammasome-dependent cytokine release

Year: 2026

Type: article

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.

Source: Cell Death and Differentiation

DOI: 10.1038/s41418-026-01769-8