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<p>Mitochondrial Ca<sup>2+</sup> uptake shapes cellular signaling by modulating metabolism, cell death and cytosolic Ca<sup>2+</sup> dynamics, yet its pathological and therapeutic relevance remains undefined. Here, we show that Ca<sup>2+</sup> entry through the mitochondrial Ca<sup>2+</sup> 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<sup>2+</sup> uptake as a key upstream signal that promotes organelle fragmentation to license inflammasome activation, positioning MCU as a potential therapeutic target in inflammatory diseases.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月27日

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  • Gaia Gherardi,
  • Francesca Spinelli,
  • Miriana Sbrissa,
  • Martina Quagliata,
  • Roberto Luisetto,
  • Anna Scanu,
  • Elena Vezzoli,
  • Michela Carraro,
  • Alva M. Casey,
  • Tiago F. Branco,
  • Naotada Ishihara,
  • Andrea Mattarei,
  • Stefano Masiero,
  • Michael P. Murphy,
  • Paolo Bernardi,
  • Carlo Tacchetti,
  • Luca Scorrano,
  • Anna Raffaello,
  • Rosario Rizzuto

摘要

Mitochondrial Ca2+ uptake shapes cellular signaling by modulating metabolism, cell death and cytosolic Ca2+ dynamics, yet its pathological and therapeutic relevance remains undefined. Here, we show that Ca2+ entry through the mitochondrial Ca2+ 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 Ca2+ uptake as a key upstream signal that promotes organelle fragmentation to license inflammasome activation, positioning MCU as a potential therapeutic target in inflammatory diseases.