2. Academic Validation
  3. Acute suppression of mitochondrial ATP production prevents apoptosis and provides an essential signal for NLRP3 inflammasome activation

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

  • Immunity. 2024 Nov 15:S1074-7613(24)00492-8. doi: 10.1016/j.immuni.2024.10.012.
Benedikt S Saller 1,  Svenja Wöhrle 2,  Larissa Fischer 2,  Clara Dufossez 2,  Isabella L Ingerl 3,  Susanne Kessler 4,  Maria Mateo-Tortola 5,  Oliver Gorka 3,  Felix Lange 6,  Yurong Cheng 7,  Emilia Neuwirt 1,  Adinarayana Marada 8,  Christoph Koentges 3,  Chiara Urban 3,  Philipp Aktories 9,  Peter Reuther 4,  Sebastian Giese 4,  Susanne Kirschnek 10,  Carolin Mayer 10,  Johannes Pilic 11,  Hugo Falquez-Medina 12,  Aline Oelgeklaus 12,  Veerasikku Gopal Deepagan 13,  Farzaneh Shojaee 13,  Julia A Zimmermann 14,  Damian Weber 15,  Yi-Heng Tai 16,  Anna Crois 17,  Kevin Ciminski 4,  Remi Peyronnet 18,  Katharina S Brandenburg 3,  Gang Wu 19,  Ralf Baumeister 20,  Thomas Heimbucher 19,  Marta Rizzi 21,  Dietmar Riedel 22,  Martin Helmstädter 23,  Joerg Buescher 24,  Konstantin Neumann 25,  Thomas Misgeld 26,  Martin Kerschensteiner 27,  Peter Walentek 15,  Clemens Kreutz 28,  Ulrich Maurer 29,  Angelika S Rambold 14,  James E Vince 13,  Frank Edlich 12,  Roland Malli 11,  Georg Häcker 10,  Katrin Kierdorf 1,  Chris Meisinger 30,  Anna Köttgen 31,  Stefan Jakobs 32,  Alexander N R Weber 33,  Martin Schwemmle 4,  Christina J Groß 34,  Olaf Groß 35
Affiliations

Affiliations

  • 1 Institute of Neuropathology, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany; Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany.
  • 2 Institute of Neuropathology, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany.
  • 3 Institute of Neuropathology, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany.
  • 4 Institute of Virology, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany.
  • 5 Department of Innate Immunity, Institute of Immunology, University of Tübingen, Tübingen, Germany.
  • 6 Research Group Mitochondrial Structure and Dynamics, Department of NanoBiophotonics, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany; Clinic for Neurology, University Medical Center of Göttingen, Göttingen, Germany.
  • 7 Institute of Genetic Epidemiology, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany.
  • 8 Institute of Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • 9 Institute of Neuropathology, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany; Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany.
  • 10 Institute of Medical Microbiology and Hygiene, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany.
  • 11 Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
  • 12 Institute of Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Veterinary Physiological Chemical Institute, Faculty of Veterinary Medicine, University of Leipzig, Leipzig, Germany.
  • 13 The Walter and Eliza Hall Institute of Medical Research, The Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
  • 14 Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
  • 15 Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany; Internal Medicine IV, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany.
  • 16 Institute of Clinical Neuroimmunology, University Hospital, Ludwig-Maximilians Universität München, Munich, Germany; Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians Universität München, Martinsried, Germany; Institute of Neuronal Cell Biology, Technical University of Munich, Munich, Germany.
  • 17 Faculty of Biology, University of Freiburg, Freiburg, Germany; Institute for Molecular Medicine and Cell Research, ZBMZ, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • 18 Institute for Experimental Cardiovascular Medicine, Faculty of Medicine, University Heart Center Freiburg - Bad Krozingen, University of Freiburg, Freiburg, Germany.
  • 19 Bioinformatics and Molecular Genetics, Faculty of Biology, University of Freiburg, Freiburg, Germany.
  • 20 Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany; Institute of Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Bioinformatics and Molecular Genetics, Faculty of Biology, University of Freiburg, Freiburg, Germany.
  • 21 Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany; Department of Rheumatology and Clinical Immunology and Center for Chronic Immunodeficiency, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany; Division of Clinical and Experimental Immunology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
  • 22 Laboratory for Electron Microscopy, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany.
  • 23 EMcore, Internal Medicine IV, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany.
  • 24 Metabolomics and FACS Core Facilities, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
  • 25 Institute of Clinical Chemistry, Hannover Medical School, Hannover, Germany.
  • 26 Institute of Neuronal Cell Biology, Technical University of Munich, Munich, Germany; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
  • 27 Institute of Clinical Neuroimmunology, University Hospital, Ludwig-Maximilians Universität München, Munich, Germany; Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians Universität München, Martinsried, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
  • 28 Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany; Institute of Medical Biometry and Statistics, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany.
  • 29 Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany; Institute for Molecular Medicine and Cell Research, ZBMZ, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • 30 Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany; Institute of Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • 31 Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany; Institute of Genetic Epidemiology, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany.
  • 32 Research Group Mitochondrial Structure and Dynamics, Department of NanoBiophotonics, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany; Clinic for Neurology, University Medical Center of Göttingen, Göttingen, Germany; Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Translational Neuroinflammation and Automated Microscopy TNM, Göttingen, Germany.
  • 33 Department of Innate Immunity, Institute of Immunology, University of Tübingen, Tübingen, Germany; Clusters of Excellence EXC-2180 (iFIT) and -2124 (CMFI), University of Tübingen, Tübingen, Germany.
  • 34 Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany.
  • 35 Institute of Neuropathology, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany; Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany. Electronic address: olaf.gross@uniklinik-freiburg.de.
PMID: 39571574 DOI: 10.1016/j.immuni.2024.10.012
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.

Keywords

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

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