Acute suppression of mitochondrial ATP production prevents apoptosis and provides an essential signal for NLRP3 inflammasome activation

How mitochondria reconcile roles in functionally divergent cell death pathways of apoptosis and NLRP3 inflammasome-mediated pyroptosis remains elusive, as is their precise role in NLRP3 activation and the evolutionarily conserved physiological function of NLRP3. Here, we have shown that when cells were challenged simultaneously, apoptosis was inhibited and NLRP3 activation prevailed. Apoptosis inhibition by structurally diverse NLRP3 activators, including nigericin, imiquimod, extracellular ATP, particles, and viruses, was not a consequence of inflammasome activation but rather of their effects on mitochondria. NLRP3 activators turned out as oxidative phosphorylation (OXPHOS) inhibitors, which we found to disrupt mitochondrial cristae architecture, leading to trapping of cytochrome c. Although this effect was alone not sufficient for NLRP3 activation, OXPHOS inhibitors became triggers of NLRP3 when combined with resiquimod or Yoda-1, suggesting that NLRP3 activation requires two simultaneous cellular signals, one of mitochondrial origin. Therefore, OXPHOS and apoptosis inhibition by NLRP3 activators provide stringency in cell death decisions.

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Publication Details

Journal
Immunity
Published
2024-11-20
DOI
https://doi.org/10.1016/j.immuni.2024.10.012
Citations
55
Primary Topic
Inflammasome and immune disorders
Type
article
Field-Weighted Citation Impact
12.86

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article

Acute suppression of mitochondrial ATP production prevents apoptosis and provides an essential signal for NLRP3 inflammasome activation

Svenja Wöhrle, Stefan Jakobs, Rémi Peyronnet, Konstantin Neumann et al.
55 citations
Immunity
Inflammasome and immune disorders
12.86
article

Acute suppression of mitochondrial ATP production prevents apoptosis and provides an essential signal for NLRP3 inflammasome activation

Svenja Wöhrle, Stefan Jakobs, Rémi Peyronnet, Konstantin Neumann, Christine Mayer, Martin Kerschensteiner, Chris Meisinger, Peter Walentek, Marta Rizzi, Susanne Kirschnek, Angelika S. Rambold, Klaus Brandenburg, Philipp Aktories, Martin Schwemmle, Alexander N.R. Weber, Johannes Pilic, James E. Vince, Emilia Neuwirt, Susanne Kessler, Adinarayana Marada, Yi-Heng Tai, Maria Mateo Tortola, Oliver Gorka, Christoph Koentges, Georg Häcker, Dominik Weber, Olaf Groß, Ralf Baumeister, Katrin Kierdorf, Dietmar Riedel, Christian Urban, Hugo Falquez-Medina, Benedikt S. Saller, Ulrich Maurer, Aline Oelgeklaus, Kevin Ciminski, Thomas Heimbucher, Roland Malli, Thomas Misgeld, Joerg M. Buescher, Clemens Kreutz, Frank Edlich, Sebastian Giese, Peter Reuther, Felix Lange, Martin Helmstädter, Gang Wu, Christina J. Groß, Julia A Zimmermann, Yurong Cheng, Larissa Fischer, Anna Köttgen, Veerasikku Gopal Deepagan, Farzaneh Shojaee, Anna Crois, Clara Dufossez, Isabella L Ingerl
article en
55 citations

Abstract

How mitochondria reconcile roles in functionally divergent cell death pathways of apoptosis and NLRP3 inflammasome-mediated pyroptosis remains elusive, as is their precise role in NLRP3 activation and the evolutionarily conserved physiological function of NLRP3. Here, we have shown that when cells were challenged simultaneously, apoptosis was inhibited and NLRP3 activation prevailed. Apoptosis inhibition by structurally diverse NLRP3 activators, including nigericin, imiquimod, extracellular ATP, particles, and viruses, was not a consequence of inflammasome activation but rather of their effects on mitochondria. NLRP3 activators turned out as oxidative phosphorylation (OXPHOS) inhibitors, which we found to disrupt mitochondrial cristae architecture, leading to trapping of cytochrome c. Although this effect was alone not sufficient for NLRP3 activation, OXPHOS inhibitors became triggers of NLRP3 when combined with resiquimod or Yoda-1, suggesting that NLRP3 activation requires two simultaneous cellular signals, one of mitochondrial origin. Therefore, OXPHOS and apoptosis inhibition by NLRP3 activators provide stringency in cell death decisions.

ImmunityVol. 58(1)
University of Freiburg (DE), Walter and Eliza Hall Institute of Medical Research (AU), Medical University of Graz (AT), University Medical Center Freiburg (DE), Medizinische Hochschule Hannover (DE), Max Planck Institute of Experimental Medicine (DE), Institute of Medical Microbiology and Hygiene (DE), Max Planck Institute of Immunobiology and Epigenetics (DE), University of Tübingen (DE)
Deutsche Forschungsgemeinschaft, European Research Council, National Health and Medical Research Council
Zero hunger
Openalex Percentile: Top 1%
Inflammasome and immune disorders
12.86
DOIOpen Access PDFOpenAlex
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