Mitochondrial damage activates the NLRP10 inflammasome.

Upon detecting pathogens or cell stress, several NOD-like receptors (NLRs) form inflammasome complexes with the adapter ASC and caspase-1, inducing gasdermin D (GSDMD)-dependent cell death and maturation and release of IL-1β and IL-18. The triggers and activation mechanisms of several inflammasome-forming sensors are not well understood. Here we show that mitochondrial damage activates the NLRP10 inflammasome, leading to ASC speck formation and caspase-1-dependent cytokine release. While the AIM2 inflammasome can also sense mitochondrial demise by detecting mitochondrial DNA (mtDNA) in the cytosol, NLRP10 monitors mitochondrial integrity in an mtDNA-independent manner, suggesting the recognition of distinct molecular entities displayed by the damaged organelles. NLRP10 is highly expressed in differentiated human keratinocytes, in which it can also assemble an inflammasome. Our study shows that this inflammasome surveils mitochondrial integrity. These findings might also lead to a better understanding of mitochondria-linked inflammatory diseases. © 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.

Citation

Tomasz Próchnicki, Matilde B Vasconcelos, Kim S Robinson, Matthew S J Mangan, Dennis De Graaf, Kateryna Shkarina, Marta Lovotti, Lena Standke, Romina Kaiser, Rainer Stahl, Fraser G Duthie, Maximilian Rothe, Kateryna Antonova, Lea-Marie Jenster, Zhi Heng Lau, Sarah Rösing, Nora Mirza, Clarissa Gottschild, Dagmar Wachten, Claudia Günther, Thomas A Kufer, Florian I Schmidt, Franklin L Zhong, Eicke Latz. Mitochondrial damage activates the NLRP10 inflammasome. Nature immunology. 2023 Apr;24(4):595-603

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PMID: 36941400

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