德国弗莱堡大学Olaf Gro课题组发现，急性抑制线粒体ATP生成可以防止细胞凋亡并为NLRP3炎症小体的激活提供重要信号。相关论文于2024年11月20日在线发表在《免疫》杂志上。

研究人员表明，当细胞同时受到挑战时，凋亡被抑制，而NLRP3的激活占主导地位。包括尼杰霉素、伊马米莫、细胞外ATP、颗粒和病毒在内的结构多样的NLRP3激活剂抑制凋亡的作用，并非源于炎症小体的激活，而是由于它们对线粒体的影响。研究人员发现，NLRP3激活剂作为氧化磷酸化（OXPHOS）抑制剂，能够破坏线粒体嵴的结构，导致细胞色素c的滞留。

尽管单独这种效应不足以激活NLRP3，但当与重组免疫模拟素（resiquimod）或Yoda-1联合使用时，OXPHOS抑制剂成为NLRP3的触发因子，提示NLRP3激活需要两个同时存在的细胞信号，其中之一来自线粒体。因此，NLRP3激活剂通过抑制OXPHOS和凋亡，在细胞死亡决策中提供了严格的选择性。

据悉，尽管线粒体在功能上具有分歧的细胞死亡途径（即凋亡和NLRP3炎症小体介导的焦亡）中的作用尚不明确，但它们在NLRP3激活和NLRP3演化上保守的生理功能中的确切角色仍不清楚。

附：英文原文

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

Author: Benedikt S. Saller, Svenja Whrle, 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 Pilic, Hugo 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 Helmstdter, 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 Hcker, Katrin Kierdorf, Chris Meisinger, Anna Kttgen, Stefan Jakobs, Alexander N.R. Weber, Martin Schwemmle, Christina J. Gro, Olaf Gro

Issue&Volume: 2024-11-20

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.

DOI: 10.1016/j.immuni.2024.10.012

Source: https://www.cell.com/immunity/abstract/S1074-7613(24)00492-8