Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
Nat Immunol. 2022 May;23(5):692-704. doi: 10.1038/s41590-022-01185-3. Epub 2022 Apr 28.
The NLRP3 inflammasome is linked to sterile and pathogen-dependent inflammation, and its dysregulation underlies many chronic diseases. Mitochondria have been implicated as regulators of the NLRP3 inflammasome through several mechanisms including generation of mitochondrial reactive oxygen species (ROS). Here, we report that mitochondrial electron transport chain (ETC) complex I, II, III and V inhibitors all prevent NLRP3 inflammasome activation. Ectopic expression of Saccharomyces cerevisiae NADH dehydrogenase (NDI1) or Ciona intestinalis alternative oxidase, which can complement the functional loss of mitochondrial complex I or III, respectively, without generation of ROS, rescued NLRP3 inflammasome activation in the absence of endogenous mitochondrial complex I or complex III function. Metabolomics revealed phosphocreatine (PCr), which can sustain ATP levels, as a common metabolite that is diminished by mitochondrial ETC inhibitors. PCr depletion decreased ATP levels and NLRP3 inflammasome activation. Thus, the mitochondrial ETC sustains NLRP3 inflammasome activation through PCr-dependent generation of ATP, but via a ROS-independent mechanism.
NLRP3 炎性小体与非感染性和感染性炎症有关，其失调是许多慢性疾病的基础。线粒体通过几种机制被认为是 NLRP3 炎性小体的调节剂，包括产生线粒体活性氧（ROS）。在这里，我们报告说，线粒体电子传递链（ETC）复合物 I、II、III 和 V 的抑制剂都能阻止 NLRP3 炎性小体的激活。酵母酿酒酵母 NADH 脱氢酶（NDI1）或海鞘替代氧化酶的异位表达，分别可以弥补线粒体复合物 I 或 III 的功能丧失，而不会产生 ROS，在没有内源性线粒体复合物 I 或 III 功能的情况下，挽救了 NLRP3 炎性小体的激活。代谢组学揭示了磷酸肌酸（PCr），它可以维持 ATP 水平，作为一种常见的代谢物，其在线粒体 ETC 抑制剂存在的情况下会减少。PCr 的耗竭降低了 ATP 水平和 NLRP3 炎性小体的激活。因此，线粒体 ETC 通过 PCr 依赖的 ATP 生成来维持 NLRP3 炎性小体的激活，但通过一种与 ROS 无关的机制。
