Mitochondrial electron transport chain is necessary for NLRP3 inflammasome activation

Leah K Billingham1, Joshua S Stoolman1, Karthik Vasan1, Arianne E Rodriguez1, Taylor A Poor1, Marten Szibor2,3,4, Howard T Jacobs2,4, Colleen R Reczek1, Aida Rashidi5, Peng Zhang5, Jason Miska5, Navdeep S Chandel6,7

  1. Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
  2. Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
  3. Department of Cardiothoracic Surgery, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany.
  4. Department of Environment and Genetics, La Trobe University, Melbourne, Victoria, Australia.
  5. Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
  6. Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. nav@northwestern.edu.
  7. Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. nav@northwestern.edu.

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.

Presented By Leah Billingham

Metabolism, Immunology & MicrobiologyNicholas Liao2022-05 (May)