Mitochondrial calcium uptake drives organelle remodeling to promote inflammasome-dependent cytokine release
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.
Authors
- Roberto Luisetto
- Anna Raffaello (ORCID: https://orcid.org/0000-0002-8344-6459)
- Rosario Rizzuto (ORCID: https://orcid.org/0000-0001-7044-5097)
- Carlo Tacchetti (ORCID: https://orcid.org/0000-0003-4602-000X)
- Miriana Sbrissa
- Alva M. Casey (ORCID: https://orcid.org/0000-0002-7242-3251)
- Elena Vezzoli (ORCID: https://orcid.org/0000-0002-3342-3451)
- Luca Scorrano (ORCID: https://orcid.org/0000-0002-8515-8928)
- Gaia Gherardi (ORCID: https://orcid.org/0000-0001-6212-3477)
- Andrea Mattarei (ORCID: https://orcid.org/0000-0002-2023-0749)
- Naotada Ishihara (ORCID: https://orcid.org/0000-0002-6305-7149)
- Anna Scanu (ORCID: https://orcid.org/0000-0001-6497-5374)
- Martina Quagliata
- Paolo Bernardi (ORCID: https://orcid.org/0000-0001-9187-3736)
- Stefano Masiero
- Michael P. Murphy
- Tiago F. Branco
- Michela Carraro (ORCID: https://orcid.org/0000-0002-4573-9306)
- Francesca Spinelli
Institutions
- University of Padua (IT)
- Vita-Salute San Raffaele University (IT)
- University of Cambridge (GB)
- National University of Rosario (AR)
- Veneto Institute of Molecular Medicine (IT)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele (IT)
- MRC Mitochondrial Biology Unit (GB)
- The University of Osaka (JP)
Publication Details
- Journal
- Cell Death and Differentiation
- Published
- 2026-05-27
- DOI
- https://doi.org/10.1038/s41418-026-01769-8
- Primary Topic
- Inflammasome and immune disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.00