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Mitochondria: master regulators of danger signalling

Nature Reviews Molecular Cell Biology volume 13, pages 780–788 (2012)Cite this article

Subjects

Key Points

  • Mitochondria not only generate the vast majority of intracellular ATP but also receive and decode organelle-extrinsic signals of stress, such as those generated during viral infection, to activate adaptive responses.

  • When homeostasis cannot be re-established, mitochondrial membranes become permeabilized, which leads to the activation of caspase-dependent and caspase-independent cell death effector mechanisms. Mitochondria regulate intrinsic apoptosis, have a prominent role in multiple instances of extrinsic apoptosis and are involved in the execution of regulated necrosis.

  • Mitochondria are capable of emitting a wide array of danger signals that alert the cell of perturbations in homeostasis. These signals include mitochondrial DNA (mtDNA), reactive oxygen species (ROS) and specific nucleus-encoded proteins, all of which activate adaptive programmes aimed at recovering mitochondrial functions.

  • In conditions of extensive tissue damage, these and other mitochondrial danger signals, such as N-formyl-peptides (NFPs), are released into the extracellular space and eventually reach the bloodstream, where they can stimulate widespread innate immune responses that can contribute to the pathophysiology of life-threatening conditions such as systemic inflammatory response syndrome (SIRS).

  • Thus, mitochondria can be considered as master regulators of cellular and systemic danger signalling.

Abstract

Throughout more than 1.5 billion years of obligate endosymbiotic co-evolution, mitochondria have developed not only the capacity to control distinct molecular cascades leading to cell death but also the ability to sense (and react to) multiple situations of cellular stress, including viral infection. In addition, mitochondria can emit danger signals that alert the cell or the whole organism of perturbations in homeostasis, hence promoting the induction of cell-intrinsic or systemic adaptive responses, respectively. As such, mitochondria can be considered as master regulators of danger signalling.

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Figure 1: Mitochondrial control of cell death.
Figure 2: Intracellular danger signals emitted by mitochondria.
Figure 3: Examples of extracellular danger signals emitted by mitochondria.

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Acknowledgements

The authors are supported by the Ligue contre le Cancer (équipe labellisée), AXA Chair for Longevity Research, Cancéropôle Ile-de-France, Institut National du Cancer (INCa), Fondation Bettencourt–Schueller, Fondation de France, Fondation pour la Recherche Médicale, Agence National de la Recherche and the European Commission (Apo-Sys, ArtForce, ChemoRes. Death-Train) and the LabEx Immuno-Oncology.

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Authors and Affiliations

  1. Université Paris V (Paris Descartes), 2 rue de l'École de Médecine, Paris, 75006, France

    Lorenzo Galluzzi & Guido Kroemer

  2. Institut Gustave Roussy, 114 rue Edouard Vaillant, Villejuif, 94805, France

    Lorenzo Galluzzi & Oliver Kepp

  3. INSERM, U848, Pavillon de Recherche 1, 39 rue Camille Desmoulins, Villejuif, 94805, France

    Oliver Kepp & Guido Kroemer

  4. Université Paris XI (Paris Sud), 63 rue Gabriel Péri, Le Kremlin-Bicêtre, 94270, France

    Guido Kroemer

  5. Metabolomics Platform, Institut Gustave Roussy, 39 rue Camille Desmoulins, Villejuif, 94805, France

    Guido Kroemer

  6. Centre de Recherche des Cordeliers, 15 rue de l'École de Médecine, Paris, 75006, France

    Guido Kroemer

  7. Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, 20 rue Leblanc, Paris, 75015, France

    Guido Kroemer

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Glossary

Pattern recognition receptors

(PRRs). Host receptors, including Toll-like receptors and NOD-like receptors, that can sense pathogen-associated molecular patterns and initiate signalling cascades that lead to an innate immune response.

Type I interferon

A group of pro-inflammatory cytokines structurally and functionally related to interferon-α that are produced in high levels by cells of the innate immune system in response to viral infection and promote the establishment of a widespread antiviral status.

Mitochondria-associated membranes

(MAMs). Sites of anatomical and functional interconnection between mitochondria and the endoplasmic reticulum.

CpG

Cytosine-guanosine DNA sequence. Unmethylated CpG sequences are prevalent in bacterial DNA but rare in eukaryotic genomes.

Systemic inflammatory response syndrome

(SIRS). A frequently lethal clinical condition that resemble sepsis in its manifestations but does not necessarily involve a microbial component.

Plasmacytoid dendritic cells

(pDCs). A subset of DCs that differ from their conventional (also known as myeloid) counterparts in morphology and in their capacity to produce copious amounts of type I interferon in response to viruses and Toll-like receptor ligands.

CD1d

A glycoprotein expressed on the surface of several antigen-presenting cells that is involved in the presentation of lipid antigens to specific subsets of T cells.

Antigen-presenting cells

(APCs). Crucial cellular components of the adaptive immune response owing to their capacity to process antigens and present antigenic peptides to T cells in the context of appropriate stimulatory signals.

Immunogenic cell death

A functionally unconventional type of apoptosis that results in the activation of an adaptive immune response against antigens from dead cells.

γδ T cells

Type of T cell bearing an unconventional T cell receptor composed of one γ-chain and one δ-chain, rather than one α-chain and one β-chain. Their antigenic repertoire is not yet well characterized, but γδ T cells seem to play a prominent part in the recognition of lipid antigens.

Sterile inflammation

Inflammatory condition that develops in the complete absence of a microbial component.

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Galluzzi, L., Kepp, O. & Kroemer, G. Mitochondria: master regulators of danger signalling. Nat Rev Mol Cell Biol 13, 780–788 (2012). https://doi.org/10.1038/nrm3479

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