Innate Immune Functions of Mitochondrial Metabolism

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Innate immunity is essential to maintain tissue homeostasis and is critical for vaccine and immunotherapy formulations. Because they express a variety of innate immune receptors, cells of the innate immune system such as macrophages or dendritic cells represent the first barrier against most, if not all infectious pathogens and tissue damages. Innate immune cell activation strongly relies on cellular metabolism reprogramming at the core of which is the mitochondrion, the main bioenergetics organelle.
The lab investigates how innate immune receptors engaged during microbial infection control mitochondrial respiratory chain and metabolism to adjust innate immune responses to the nature of threat encountered. We thereby seek at alleviating an important hurdle to vaccine design and therapeutic treatment of bacterial infections, inflammatory diseases or mitochondrial disorders.

Mitochondrial electron transport chain (ETC) adaptations during microbial infection

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The ETC comprises two electron carriers (coenzyme Q [CoQ]/ubiquinone and cytochrome c) and four respiratory complexes (complex I to IV [CI to CIV]), which, except for CII, can dynamically assemble as larger molecular supercomplexes (SCs) in the mitochondrial inner membrane. This dynamic assembly of respiratory complexes into SCs has been proposed to confer functional advantages to the cells but its relevance for innate immunity is still unknown. We aim at providing the molecular details that govern ETC and metabolic adjustments evoked during antibacterial immunity. We pay a particular attention to the contribution of innate immune receptors such as the Toll-like receptors in regulating this process.

The metabolic cross-talk of host-pathogen interactions

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The innate immune system closely interacts with microbes to either establish mutualism or eradicate the threat in the case of pathogenic microbes. This interaction is based on exchange a multitude of molecules among which metabolites are emerging as key regulators. We are investigating the molecular determinants that allow innate immune cell metabolism to integrate the metabolic characteristic of microbes.

Innate immune dysfunctions in mitochondrial disorders

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Mitochondrial metabolism has recently emerged as a fundamental component of immune responses. Yet, very few data from clinical studies are available and hematological consequences of mitochondrial dysfunctions are largely unknown. Notably, immune dysfunction is not currently included in clinical diagnostic criteria for mitochondrial disorders although remarkable rates of infections have been noted in cohorts from two primary mitochondrial diseases. Using patient samples, we assess the impact of ETC dysfunctions on innate immunity, antibacterial capacity and antigen presentation. Our objective is to provide clinically-relevant information on the immune consequences of mitochondrial diseases to alleviate hospitalization burden.

Contributing Members

Johan Garaude [INSERM Associate Researcher, Principal Investigator]
Khaddouj Benmoussa [Postdoc Researcher]
Aurélia Brillac-Coronas [Engineer]
Juliette Lesbats [PhD Student]
Gaia Tioli [PhD Student, co-supervised with M.L. GENOVA, University of Bologna, Italy]

National and International Collaborations

Nicolas Manel [Institut Curie, Paris, France]
Leif E. Sander [La charité Hospital, Berlin, Germany]
Maria Luisa Genova [University of Bologna, Italy]
José Antonio Enríquez [CNIC, Madrid, Spain]

Project publications

Garaude J. Reprogramming of mitochondrial metabolism by innate immunity. Current Opinion in Immunoogyl. 2018. https://doi.org/10.1016/j.coi.2018.09.010

Benmoussa, K., Garaude J.$ and Acín-Pérez, R. $ How mitochondrial metabolism contributes to macrophage functions. Journal of Molecular Biology. 2018. [$ Corresponding authors]
https://doi.org/10.1016/j.jmb.2018.07.003

Sander L.E.$ and Garaude J.$. The mitochondrial respiratory chain: a metabolic rheostat of antibacterial immunity. Mitochondrion. 2017 Oct 17. [$ Corresponding authors]
https://doi.org/10.1016/j.mito.2017.10.008

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.$. Mitochondrial respiratory-chain adaptions in macrophages contribute to antibacterial host defence. Nature Immunology. 2016. [* Equal contributions] [$ Corresponding authors]
https://doi.org/10.1038/ni.3509

Highlights in Nature Immunology by G. Shadel and in Nature Reviews Immunology.

Comments in Science Signaling.

Highlights in Nature Reviews Immunology.

Garaude J., Kent A., van Rooijen N., & Blander J.M. Simultaneous targeting of toll- and nod-like receptors induces effective tumor-specific immune response. Sci. Transl. Med. 2012 Feb 8. 4(120):120ra16. Cover article + Editors choice.
https://doi.org/10.1126/scitranslmed.3002868

Comments in Science Translational Medicine by J.A. Berzofsky (Vol.4 issue 120)