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

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

Research output: Contribution to journalArticlepeer-review

1 Scopus 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.

Original languageEnglish
Pages (from-to)90-107.e11
JournalImmunity
Volume58
Issue number1
DOIs
StatePublished - 14 Jan 2025

Keywords

  • ATP
  • NLRP3
  • OXPHOS
  • apoptosis
  • bioenergetics
  • cell death
  • chemical biology
  • cytochrome c
  • inflammasome
  • mitochondria
  • pyroptosis

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