Mitochondrial cardiolipin is required for Nlrp3 inflammasome activation

By S. Iyer, Qiong He, J. R. Janczy, Eric I. Elliott, Zhenyu Zhong, A. Olivier, J. Sadler, Vickie Knepper-Adrian, Renzhi Han, L. Qiao and 4 more. Immunity, 2013

866 citations recorded by the source corpus.

Summary Nlrp3 inflammasome activation occurs in response to numerous agonists but the specific mechanism by which this takes place remains unclear. All previously evaluated activators of the Nlrp3 inflammasome induce the generation of mitochondrial reactive oxygen species (ROS), suggesting a model in which ROS is a required upstream mediator of Nlrp3 inflammasome activation. Here we have identified the oxazolidinone antibiotic, linezolid, as a Nlrp3 agonist that activates the Nlrp3 inflammasome independently of ROS. The pathways for ROS-dependent and ROS-independent Nlrp3 activation converged upon mitochondrial dysfunction and specifically the mitochondrial lipid cardiolipin. Cardiolipin bound to Nlrp3 directly and interference with cardiolipin synthesis specifically inhibited Nlrp3 inflammasome activation. Together these data suggest that mitochondria play a critical role in the activation of the Nlrp3 inflammasome through the direct binding of Nlrp3 to cardiolipin.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/e804abc42b82bff8feadd384a07fae2d373e7a49

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In Molecular Biology

1. T. Kanneganti
2. Guido Kroemer
3. L. Galluzzi
4. Douglas R. Green
5. M. Lamkanfi
6. G. Núñez
7. S. Man
8. Yuan He

Citations in the corpus

• An update on the regulatory mechanisms of NLRP3 inflammasome activation (2021, background): “Cardiolipin binds directly to the LRR domain of NLRP3 and provides an activating signal for NLRP3 inflammasome complex assembly and activation.(123,125) A deeper, context-dependent understanding of the roles of mtROS and mtDNA and the interaction of NLRP3 components with mitochondrial molecules is r”
• Regulation of inflammasome activation (2015, background): “A number of mechanisms have been proposed, including mitochondrial-associated dysfunction [mitochondrial reactive oxygen species (ROS) (49), oxidized mitochondrial DNA (50), translocation of cardiolipin from the inner to the outer mitochondrial membrane (51)], potassium efflux (52–54), an increase i”
• Inflammation following acute myocardial infarction: Multiple players, dynamic roles, and novel therapeutic opportunities (2018, background): “The release of ATP can activate the P2X7 membrane receptor thereby inducing efflux of intracellular potassium, the release of mitochondrial cardiolipin and subsequent NLRP3-inflammasome activation (Iyer et al., 2013; Mariathasan et al., 2006).”
• Mechanisms and functions of inflammasomes. (2014, background): “…production of mitochondrial reactive oxygen species (Zhou et al., 2011), (4) the release of mitochondrial DNA or the mitochondrial phospholipid cardiolipin (Iyer et al., 2013; Nakahira et al., 2011; Shimada et al., 2012), and (5) the cytosolic release of lysosomal cathepsins (Hornung et al., 2008).”
• The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation (2019, background): “Cardiolipin, which is a lipid of the inner mitochondrial membrane, was shown to externalize and bind directly to the LRR domain of NLRP3, and disrupting cardiolipin expression is detrimental to NLRP3 activation [107].”
• Initiation and perpetuation of NLRP3 inflammasome activation and assembly (2015, background): “Cyclosporine A (CsA) strongly inhibits NLRP3 inflammasome activation, but this inhibition may be independent of its effects on cyclophilin D (CypD)-mediated MPT (105, 106, 127).”
• Metabolic control of cell death (2014, background): “Among various proteins that have been suggested to compose the PTPC, including ANT and voltage-dependent anion channel (VDAC, an OMM-embedded protein), so far only CYPD has been ascribed with a critical role in MPT (30) Partial depletion of PIC also fails to affect MPT. Conversely, the knockdown of ”
• NLRP3 inflammasome and its inhibitors: a review (2015, background): “These include mitochondrial damage or dysfunction caused by mitochondrial Ca2+ overload (Iyer et al., 2013; Miao et al., 2014; Zhuang et al., 2015), lysosomal disruption (Hornung et al., 2008; Sheedy et al., 2013; Tseng et al., 2013), autophagic dysfunction (Cho et al., 2014; Shao et al., 2014;…”
• Mitochondrial dysfunction in pathophysiology of heart failure (2018, background): “org Volume 128 Number 9 September 2018 lar patterns (DAMPs) triggers an inflammatory response (21, 141, 142).”