Mitochondrial respiratory-chain adaptations in macrophages contribute to antibacterial host defense
Open accessAbstract
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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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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Self-citation
- 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
- ORCID
- Venue
- Nature Immunology
- Published
- 2016-06-27
- Volume
- 17
- Issue
- 9
- Pages
- 1037-1045
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC4994870
- 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
- green
- doi.org
- Licence
- cc-by-nc-nd
- www.springer.com/tdm (tdm)
- 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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