Mitochondrial electron transport chain is necessary for NLRP3 inflammasome activation

Leah K. Billingham; Joshua S. Stoolman; Karthik Vasan; Arianne E. Rodriguez; Taylor A. Poor; Marten Szibor; Howard T. Jacobs; Colleen R. Reczek; Aida Rashidi; Peng Zhang; Jason Miska; Navdeep S. Chandel

doi:10.1038/s41590-022-01185-3

Mitochondrial electron transport chain is necessary for NLRP3 inflammasome activation

Leah K. Billingham
, Joshua S. Stoolman
, Karthik Vasan
, Arianne E. Rodriguez
, Taylor A. Poor
, Marten Szibor
, Howard T. Jacobs
, Colleen R. Reczek
, Aida Rashidi
, Peng Zhang
, Jason Miska
, Navdeep S. Chandel^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Scientific › peer-review

322 Citations (Scopus)

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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.

Original language	English
Pages (from-to)	692–704
Number of pages	39
Journal	Nature Immunology
Volume	23
Issue number	5
Early online date	2022
DOIs	https://doi.org/10.1038/s41590-022-01185-3
Publication status	Published - 2022
Publication type	A1 Journal article-refereed

Funding

This work was supported by the National Institutes for Health (NIH) (5R35CA197532, 5P01HL071643-15 and 5PO1AG049665) to N.S.C.; L.K.B. was supported by the NIH/National Heart, Lung, and Blood Institute (NHLBI) (T32HL076139-15). J.M. was supported by the NIH (1R01NS115955-01). J.S.S. was supported by the NIH/National Institute of Allergy and Infectious Diseases (NIAID) T32 (T32AI083216). Additional support from the NIH (F30CA250236) to K.V., NIH/NHLBI T32HL076139-17 to T.A.P. and the Ford Foundation to A.E.R. We thank the Robert H. Lurie Cancer Center Flow Cytometry facility and Metabolomics Core supported by National Cancer Institute Cancer Center Support Grant (NCI CCSG) P30 CA060553 for their invaluable assistance. We thank P. Gao at Northwestern University for his expertise in metabolomics. We thank H. Abdala-Valencia at Northwestern University for RNA sequencing. We thank O. Grob at University of Freiburg for his helpful comments and discussion of the paper. Some figure elements were generated with biorender.com.

Publication forum classification

Publication forum level 3

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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s41590-022-01185-3Final published version, 5.5 MBLicence: CC BY

https://urn.fi/URN:NBN:fi:tuni-202205174985Licence: CC BY

Cite this

@article{7d2b9955a89845368aab0b8b23788e13,

title = "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.",

author = "Billingham, \{Leah K.\} and Stoolman, \{Joshua S.\} and Karthik Vasan and Rodriguez, \{Arianne E.\} and Poor, \{Taylor A.\} and Marten Szibor and Jacobs, \{Howard T.\} and Reczek, \{Colleen R.\} and Aida Rashidi and Peng Zhang and Jason Miska and Chandel, \{Navdeep S.\}",

note = "Funding Information: This work was supported by the National Institutes for Health (NIH) (5R35CA197532, 5P01HL071643-15 and 5PO1AG049665) to N.S.C.; L.K.B. was supported by the NIH/National Heart, Lung, and Blood Institute (NHLBI) (T32HL076139-15). J.M. was supported by the NIH (1R01NS115955-01). J.S.S. was supported by the NIH/National Institute of Allergy and Infectious Diseases (NIAID) T32 (T32AI083216). Additional support from the NIH (F30CA250236) to K.V., NIH/NHLBI T32HL076139-17 to T.A.P. and the Ford Foundation to A.E.R. We thank the Robert H. Lurie Cancer Center Flow Cytometry facility and Metabolomics Core supported by National Cancer Institute Cancer Center Support Grant (NCI CCSG) P30 CA060553 for their invaluable assistance. We thank P. Gao at Northwestern University for his expertise in metabolomics. We thank H. Abdala-Valencia at Northwestern University for RNA sequencing. We thank O. Grob at University of Freiburg for his helpful comments and discussion of the paper. Some figure elements were generated with biorender.com. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

doi = "10.1038/s41590-022-01185-3",

language = "English",

volume = "23",

pages = "692–704",

journal = "Nature Immunology",

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T1 - Mitochondrial electron transport chain is necessary for NLRP3 inflammasome activation

AU - Billingham, Leah K.

AU - Stoolman, Joshua S.

AU - Vasan, Karthik

AU - Rodriguez, Arianne E.

AU - Poor, Taylor A.

AU - Szibor, Marten

AU - Jacobs, Howard T.

AU - Reczek, Colleen R.

AU - Rashidi, Aida

AU - Zhang, Peng

AU - Miska, Jason

AU - Chandel, Navdeep S.

N1 - Funding Information: This work was supported by the National Institutes for Health (NIH) (5R35CA197532, 5P01HL071643-15 and 5PO1AG049665) to N.S.C.; L.K.B. was supported by the NIH/National Heart, Lung, and Blood Institute (NHLBI) (T32HL076139-15). J.M. was supported by the NIH (1R01NS115955-01). J.S.S. was supported by the NIH/National Institute of Allergy and Infectious Diseases (NIAID) T32 (T32AI083216). Additional support from the NIH (F30CA250236) to K.V., NIH/NHLBI T32HL076139-17 to T.A.P. and the Ford Foundation to A.E.R. We thank the Robert H. Lurie Cancer Center Flow Cytometry facility and Metabolomics Core supported by National Cancer Institute Cancer Center Support Grant (NCI CCSG) P30 CA060553 for their invaluable assistance. We thank P. Gao at Northwestern University for his expertise in metabolomics. We thank H. Abdala-Valencia at Northwestern University for RNA sequencing. We thank O. Grob at University of Freiburg for his helpful comments and discussion of the paper. Some figure elements were generated with biorender.com. Publisher Copyright: © 2022, The Author(s).

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N2 - 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.

AB - 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.

U2 - 10.1038/s41590-022-01185-3

DO - 10.1038/s41590-022-01185-3

M3 - Article

AN - SCOPUS:85128909936

SN - 1529-2908

VL - 23

SP - 692

EP - 704

JO - Nature Immunology

JF - Nature Immunology

IS - 5

ER -

Mitochondrial electron transport chain is necessary for NLRP3 inflammasome activation

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