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  • Review Article
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The role of mitochondria in rheumatic diseases

Nature Reviews Rheumatology volume 18, pages 621–640 (2022)Cite this article

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Abstract

The mitochondrion is an intracellular organelle thought to originate from endosymbiosis between an ancestral eukaryotic cell and an α-proteobacterium. Mitochondria are the powerhouses of the cell, and can control several important processes within the cell, such as cell death. Conversely, dysregulation of mitochondria possibly contributes to the pathophysiology of several autoimmune diseases. Defects in mitochondria can be caused by mutations in the mitochondrial genome or by chronic exposure to pro-inflammatory cytokines, including type I interferons. Following the release of intact mitochondria or mitochondrial components into the cytosol or the extracellular space, the bacteria-like molecular motifs of mitochondria can elicit pro-inflammatory responses by the innate immune system. Moreover, antibodies can target mitochondria in autoimmune diseases, suggesting an interplay between the adaptive immune system and mitochondria. In this Review, we discuss the roles of mitochondria in rheumatic diseases such as systemic lupus erythematosus, antiphospholipid syndrome and rheumatoid arthritis. An understanding of the different contributions of mitochondria to distinct rheumatic diseases or manifestations could permit the development of novel therapeutic strategies and the use of mitochondria-derived biomarkers to inform pathogenesis.

Key points

  • Mitochondrial DNA mutations can affect mitochondrial function and lead or contribute to diseases, including rheumatic diseases.

  • Mitochondria are involved in the regulation of several important processes, including cell death.

  • Mitochondria contain numerous bacterial-like molecules that are able to trigger inflammatory responses by the innate immune system.

  • Increased levels of extracellular mitochondria are observed in patients with rheumatic diseases and are thought to contribute to disease.

  • Mitochondria are immunogenic, and anti-mitochondrial antibodies (for example, antibodies that target cardiolipin, mitofusin 1, mitochondrial DNA or mitochondrial RNA) are commonly seen in patients with rheumatic diseases.

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Fig. 1: Mitochondrial morphology and organization of mitochondrial DNA.
Fig. 2: Mitochondrial dynamics and regulation of the mitochondrial network by fusion and fission.
Fig. 3: Mitophagy regulates the mitochondrial mass during erythrocyte maturation.
Fig. 4: The various roles of the mitochondrion in inflammation.
Fig. 5: The role of extracellular mitochondria in SLE pathophysiology.
Fig. 6: Mitochondrial antigen presentation by MHC molecules in autoimmune diseases.

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Acknowledgements

Y.L.C.B. is supported by a fellowship from the Fonds de Recherche du Québec en Santé (FRQS). P.R.F. holds the tier 1 Canada Research Chair in Systemic Autoimmune Rheumatic Diseases. C.L. is supported by awards from the NIH (1 R21 AR077565, 1 R21 AR079542 and 1 R01 HL158606). E.B. is supported by a senior award from the FRQS.

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Author notes

  1. These authors contributed equally: Yann L.C. Becker and Bhargavi Duvvuri.

Authors and Affiliations

  1. Centre de Recherche ARThrite-Arthrite, Recherche et Traitements, Université Laval, Québec, QC, Canada

    Yann L. C. Becker, Paul R. Fortin & Eric Boilard

  2. Centre de Recherche du CHU de Québec-Université Laval, Axe Maladies infectieuses et immunitaires, Québec, QC, Canada

    Yann L. C. Becker, Paul R. Fortin & Eric Boilard

  3. Département de microbiologie et immunologie, Université Laval, Québec, QC, Canada

    Yann L. C. Becker & Eric Boilard

  4. Division of Rheumatology, University of Washington, Seattle, WA, USA

    Bhargavi Duvvuri & Christian Lood

  5. Division of Rheumatology, Department of Medicine, CHU de Québec–Université Laval, Québec, QC, Canada

    Paul R. Fortin

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Contributions

E.B., Y.L.C.B., B.D. and C.L. researched data for the article and wrote the article. All authors contributed substantially to discussion of the content and reviewed and/or edited the manuscript before submission.

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Correspondence to Christian Lood or Eric Boilard.

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Y.L.C.B., P.R.F. and E.B. have filed a provisional patent regarding kits to detect anti-mitochondrial antibodies in systemic lupus erythematosus. The remaining authors declare no competing interests.

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Nature Reviews Rheumatology thanks F. Blanco, A. Perl and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Endosymbiotic hypothesis

A hypothesis stating that mitochondria originate from the symbiosis between a primitive eukaryote and a bacterium.

Neutrophil extracellular trap (NET) formation

An immune mechanism in which activated neutrophils release a reticular structure comprising nucleic acids and proteins intended to trap pathogens.

Waste disposal hypothesis

A hypothesis stating that complement-mediated elimination of apoptotic debris helps to prevent autoimmune response to self-antigens.

Spare respiratory capacity

The quantity of extra ATP that might be produced by mitochondria, indicating the bioenergetic fitness of cells to withstand conditions of high-energy demand such as antigenic challenge or stress.

Mitophagy

A pathway derived from autophagy, dedicated to the degradation of damaged or supernumerary mitochondria.

Mitochondrial fusion

The merging of two organelles into one single mitochondrion.

Mitochondrial fission

The scission of one mother mitochondrion into two daughter mitochondria.

Megamitochondria

An abnormally large mitochondrion, associated with oxidative stress and apoptosis.

Necroptosis

A programmed form of cell death by necrosis that, unlike apoptosis, elicits pro-inflammatory reactions.

Necrosis

A form of cell death, associated with the pro-inflammatory release of cytosolic content into the extracellular space.

Pyroptosis

A pro-inflammatory type of programmed cell death.

Transmitophagy

Cell-to-cell transmission of mitochondria.

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Becker, Y.L.C., Duvvuri, B., Fortin, P.R. et al. The role of mitochondria in rheumatic diseases. Nat Rev Rheumatol 18, 621–640 (2022). https://doi.org/10.1038/s41584-022-00834-z

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