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

Benedikt S Saller¹, Svenja Wöhrle², Larissa Fischer², Clara Dufossez², Isabella L Ingerl³, Susanne Kessler⁴, Maria Mateo-Tortola⁵, Oliver Gorka³, Felix Lange⁶, Yurong Cheng⁷, Emilia Neuwirt¹, Adinarayana Marada⁸, Christoph Koentges³, Chiara Urban³, Philipp Aktories⁹, Peter Reuther⁴, Sebastian Giese⁴, Susanne Kirschnek¹⁰, Carolin Mayer¹⁰, Johannes Pilic¹¹, Hugo Falquez-Medina¹², Aline Oelgeklaus¹², Veerasikku Gopal Deepagan¹³, Farzaneh Shojaee¹³, Julia A Zimmermann¹⁴, Damian Weber¹⁵, Yi-Heng Tai¹⁶, Anna Crois¹⁷, Kevin Ciminski⁴, Remi Peyronnet¹⁸, Katharina S Brandenburg³, Gang Wu¹⁹, Ralf Baumeister²⁰, Thomas Heimbucher¹⁹, Marta Rizzi²¹, Dietmar Riedel²², Martin Helmstädter²³, Joerg Buescher²⁴, Konstantin Neumann²⁵, Thomas Misgeld²⁶, Martin Kerschensteiner²⁷, Peter Walentek¹⁵, Clemens Kreutz²⁸, Ulrich Maurer²⁹, Angelika S Rambold¹⁴, James E Vince¹³, Frank Edlich¹², Roland Malli¹¹, Georg Häcker¹⁰, Katrin Kierdorf¹, Chris Meisinger³⁰, Anna Köttgen³¹, Stefan Jakobs³², Alexander N R Weber³³, Martin Schwemmle⁴, Christina J Groß³⁴, Olaf Groß³⁵

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

Free article

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

Benedikt S Saller et al. Immunity. 2025.

Free article

. 2025 Jan 14;58(1):90-107.e11.

doi: 10.1016/j.immuni.2024.10.012. Epub 2024 Nov 20.

Authors

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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Conflict of interest statement

Declaration of interests E.N. and O. Groß are coinventors on patent applications for immunomodulators and co-founders of EMUNO Therapeutics, a company developing drugs that control immunity to address unmet clinical needs. None of the drug candidates in patenting or development were used in this study.

Comment in

Mitochondria and NLRP3: To die or inflame.
Yang S, Huang G, Ting JP. Yang S, et al. Immunity. 2025 Jan 14;58(1):5-7. doi: 10.1016/j.immuni.2024.12.007. Immunity. 2025. PMID: 39813994 Free PMC article.

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

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

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