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

Saller, BS; Wohrle, S; Fischer, L; Dufossez, C; Ingerl, IL; Kessler, S; Mateo-Tortola, M; Gorka, O; Lange, F; Cheng, Y; Neuwirt, E; Marada, A; Koentges, C; Urban, C; Aktories, P; Reuther, P; Giese, S; Kirschnek, S; Mayer, C; Pilic, J; Falquez-Medina, H; Oelgeklaus, A; Deepagan, VG; Shojaee, F; Zimmermann, JA; Weber, D; Tai, YH; Crois, A; Ciminski, K; Peyronnet, R; Brandenburg, KS; Wu, G; Baumeister, R; Heimbucher, T; Rizzi, M; Riedel, D; Helmstadter, M; Buescher, J; Neumann, K; Misgeld, T; Kerschensteiner, M; Walentek, P; Kreutz, C; Maurer, U; Rambold, AS; Vince, JE; Edlich, F; Malli, R; Hacker, G; Kierdorf, K; Meisinger, C; Kottgen, A; Jakobs, S; Weber, ANR; Schwemmle, M; Gross, CJ; Gross, O

Author(s): Saller, BS; Wohrle, S; Fischer, L; Dufossez, C; Ingerl, IL; Kessler, S; Mateo-Tortola, M; Gorka, O; Lange, F; Cheng, Y; Neuwirt, E; Marada, A; Koentges, C; Urban, C; Aktories, P; Reuther, P; Giese, S; Kirschnek, S; Mayer, C; Pilic, J; Falquez-Medina, H; Oelgeklaus, A; Deepagan, VG; Shojaee, F; Zimmermann, JA; Weber, D; Tai, YH; Crois, A; Ciminski, K; Peyronnet, R; Brandenburg, KS; Wu, G; Baumeister, R; Heimbucher, T; Rizzi, M; Riedel, D; Helmstadter, M; Buescher, J; Neumann, K; Misgeld, T; Kerschensteiner, M; Walentek, P; Kreutz, C; Maurer, U; Rambold, AS; Vince, JE; Edlich, F; Malli, R; Hacker, G; Kierdorf, K; Meisinger, C; Kottgen, A; Jakobs, S; Weber, ANR; Schwemmle, M; Gross, CJ; Gross, O;
Details: Publication Year 2025-01-14,Volume 58,Issue #1,Page 90-107 e11
Journal Title: Immunity
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: *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism; *Inflammasomes/metabolism; *Mitochondria/metabolism; *Apoptosis; *Adenosine Triphosphate/metabolism; Animals; Mice; *Oxidative Phosphorylation; Humans; Signal Transduction; Mice, Inbred C57BL; Pyroptosis; Atp; Nlrp3; Oxphos; apoptosis; bioenergetics; cell death; chemical biology; cytochrome c; inflammasome; mitochondria
Research Division(s): Inflammation
PubMed ID: 39571574
Publisher's Version: https://doi.org/10.1016/j.immuni.2024.10.012
Open Access at Publisher's Site: https://doi.org/10.1016/j.immuni.2024.10.012
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-01-21 10:07:52

Last Modified: 2025-01-21 11:03:01