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

Saller, Benedikt S.; Wöhrle, Svenja; Fischer, Larissa; Dufossez, Clara; Ingerl, Isabella L.; Kessler, Susanne; Mateo Tortola, Maria; Gorka, Oliver; Lange, Felix; Cheng, Yurong; Neuwirt, Emilia; Marada, Adinarayana; Koentges, Christoph; Urban, Chiara; Aktories, Philipp; Reuther, Peter; Giese, Sebastian; Kirschnek, Susanne; Mayer, Carolin; Pilic, Johannes; Falquez Medina, Hugo; Oelgeklaus, Aline; Deepagan, Veerasikku Gopal; Shojaee, Farzaneh; Zimmermann, Julia A.; Weber, Damian; Tai, Yi-Heng; Crois, Anna; Ciminski, Kevin; Peyronnet, Remi; Brandenburg, Katharina S.; Wu, Gang; Baumeister, Ralf; Heimbucher, Thomas; Rizzi, Marta; Riedel, Dietmar; Helmstädter, Martin; Buescher, Joerg; Neumann, Konstantin; Misgeld, Thomas ; Kerschensteiner, Martin ; Walentek, Peter; Kreutz, Clemens; Maurer, Ulrich; Rambold, Angelika S.; Vince, James E.; Edlich, Frank; Malli, Roland; Häcker, Georg; Kierdorf, Katrin; Meisinger, Chris; Köttgen, Anna; Jakobs, Stefan; Weber, Alexander N. R.; Schwemmle, Martin; Groß, Christina J. und Groß, Olaf (2025): Acute suppression of mitochondrial ATP production prevents apoptosis and provides an essential signal for NLRP3 inflammasome activation. In: Immunity, Vol. 58, No. 1: pp. 90-107

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.

• Item Type: Journal article
• Faculties: Medicine > Munich Cluster for Systems Neurology (SyNergy); Medicine > Institute for Stroke and Dementia Research (ISD); Medicine > Medical Center of the University of Munich; Medicine > Medical Center of the University of Munich > Neurological Clinic and Polyclinic with Friedrich Baur Institute
• Subjects: 600 Technology > 610 Medicine and health
• ISSN: 1074-7613
• Language: English
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198