Mitochondrial electron transport chain is necessary for NLRP3 inflammasome activation

Abstract

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.

Macrophage Innate Training Induced by IL-4 and IL-13 Activation Enhances OXPHOS Driven Anti-Mycobacterial Responses

“…In the present study, it was moreover observed that the use of a glutaminolysis inhibitor reduced TNFα and IL-6 secretion following secondary stimulation in trained M(4/13) specifically, and not in untrained M(-) or M(IFNγ/LPS) (Figure 4A). This work suggests that OXPHOS can be important for pro-inflammatory responses, an observation that is supported by previous work demonstrating that for instance mitochondrial stress is a mechanism of macrophage tolerance (Timblin et al, 2021) and that the ETC is important for nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activity (Billingham et al, 2022). It should be noted that in the latter study however, LPS induced TNFα secretion was not impeded by inhibition of ETC complexes I and II, demonstrating once more that the metabolic phenotype of the trained M(4/13), explored in the current study, is highly unexpected and warrants further study.…”

Mitochondrial control of inflammation

“…Interestingly, although various ROS-dependent mechanisms have been invoked to sustain NLRP3 inflammasome signalling downstream of mitochondrial dysfunction 72 , ROS inhibitors seem to disrupt inflammasome priming (the synthesis of inflammasome components), but not activation (the acquisition of proteolytic activity) 73 . In line with this notion, recent data suggest that oxidative phosphorylation is involved in NLRP3 signalling driven by acute exposure to bacterial lipopolysaccharide (LPS) plus ATP 74 through a ROS-independent mechanism linked to preserved intracellular ATP availability via phosphocreatine 75 , although ROS seem to be necessary for long-term inflammasome activation upon prolonged exposure to β-amyloid. Moreover, conventional inflammasome activators such as LPS plus ATP seem to (elicit and) require mtDNA neosynthesis for optimal NLRP3 inflammasome signalling 76 .…”

Activation and Pharmacological Regulation of Inflammasomes

“…During severe fever upon thrombocytopenia syndrome virus (SFTSV) infection, mtDNA is released into the cytosol through BAK/BAX signaling, which activates the NLRP3 inflammasome [ 128 ]. Moreover, the mitochondrial electron transport chain (ETC) is essential for NLRP3 inflammasome activation through the phosphocreatine-dependent generation of ATP [ 129 ].…”