Cited by 313Immune Response and InflammationMitochondrial Function and PathologyNeutrophil, Myeloperoxidase and Oxidative Mechanisms

Mitochondrial respiratory-chain adaptations in macrophages contribute to antibacterial host defense

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Garaude, Johan, Acín-Pérez, Rebeca, Martínez-Cano, Sarai, Enamorado, Michel, Ugolini, Matteo, Nistal-Villán, Estanislao, Hervás-Stubbs, Sandra, Pelegrín, Pablo +3 more·2016·Nature Immunology

Abstract

Macrophages tightly scale their core metabolism after being activated, but the precise regulation of the mitochondrial electron-transport chain (ETC) and its functional implications are currently unknown. Here we found that recognition of live bacteria by macrophages transiently decreased assembly of the ETC complex I (CI) and CI-containing super-complexes and switched the relative contributions of CI and CII to mitochondrial respiration. This was mediated by phagosomal NADPH oxidase and the reactive oxygen species (ROS)-dependent tyrosine kinase Fgr. It required Toll-like receptor signaling and the NLRP3 inflammasome, which were both connected to bacterial viability-specific immune responses. Inhibition of CII during infection with Escherichia coli normalized serum concentrations of interleukin 1β (IL-1β) and IL-10 to those in mice treated with dead bacteria and impaired control of bacteria. We have thus identified ETC adaptations as an early immunological-metabolic checkpoint that adjusts innate immune responses to bacterial infection.

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Crossref · 10.1038/ni.3509

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  • E.c. infection of BMDM caused reduced complex I activity but enhanced complex II activity, and induced no matrix mtROS production.

    “In BMDM infected with E.c., mitochondria showed reduced complex I activity but enhanced complex II activity. While induction of matrix mtROS with rotenone [269], a commonly used positive control for matrix mtROS measurements (see Section 5.2 and Section 7) [30,270,271], was still possible, E.c. infection induced no matrix mtROS production suggesting that the activity shift to complex II did not”

    From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [268]

  • FGR is critical for increasing complex II activity.

    “The mitochondria-located feline gardner-rasheed tyrosine kinase (FGR) was critical for increasing complex II activity, since FGR-deficient BMDM showed reduced complex II activity.”

    From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [268]

  • Nox2-deficient BMDM showed reduced complex II activity, suggesting a signaling function of Nox2-derived extracellular ROS in ETC rearrangement.

    “Notably, Nox2-deficient BMDM also showed reduced complex II activity suggesting a signaling function of Nox2-derived extracellular ROS in ETC rearrangement.”

    From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [268]

  • Nox2-deficient BMDM completely failed to produce extracellular ROS after E.c. infection.

    “By contrast, extracellular ROS production induced by E.c infection was by Nox2 since Nox2-deficient BMDM completely failed to produce extracellular ROS after infection.”

    From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [268]

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Authors
Garaude, J., Acín-Pérez, R., Martínez-Cano, S., Enamorado, M., Ugolini, M., Nistal-Villán, E., Hervás-Stubbs, S., Pelegrín, P., Sander, L. E., Enríquez, J. A., & Sancho, D.
Affiliations
  • Spanish National Centre for Cardiovascular Research (ES)
  • Stiftung Charité (DE)
Corresponding author
  • Garaude, Johan
  • Sancho, David
Venue
Nature Immunology
Published
2016-06-27
Volume
17
Issue
9
Pages
1037-1045
ISSN
  • 1529-2908 (ISSN-L)
  • 1529-2916
OpenAlex
W2463549330
Cited by
313
References
49
Citations by year
2026: 25 · 2025: 26 · 2024: 31 · 2023: 27 · 2022: 25 · 2021: 45 · 2020: 38 · 2019: 37 · 2018: 30 · 2017: 21 · 2016: 7 · 2012: 1
FWCI
19.16
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Immunology (publishedVersion)
  • PubMed (publishedVersion)
  • Hispana (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • HAL (submittedVersion)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
Keywords
macrophages, mitochondrial electron transport chain, complex I, complex II, supercomplexes, reactive oxygen species, Toll-like receptor signaling, NLRP3 inflammasome, Escherichia coli infection, IL-1β, IL-10
MeSH terms
NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Cells, Cultured, Energy Metabolism, Escherichia coli Infections, Host-Parasite Interactions, Immunity, Innate, Macrophages, Mice, Inbred C57BL, Mitochondria, Phagocytosis, Interleukin-10, Reactive Oxygen Species, Mice, Knockout, Electron Transport Chain Complex Proteins, Escherichia coli K12, Mice, Interleukin-1beta

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