Jens Staal
Luz Pamela Blanco
Andras Perl- 1Unit of Molecular Signal Transduction in Inflammation, Flemmish Institute of Biotechnology (VIB)-UGent Center for Inflammation Research, Ghent, Belgium
- 2Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
- 3Department of Biochemistry and Microbiology, Ghent University, Ghent, Belgium
- 4The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD, United States
- 5Department of Medicine, Upstate Medical University, Syracuse, NY, United States
- 6Department of Biochemistry and Molecular Biology, Upstate Medical University, Syracuse, NY, United States
- 7Department of Microbiology and Immunology, Upstate Medical University, Syracuse, NY, United States
Editorial on the Research Topic
Mitochondrial dysfunction in inflammation and autoimmunity
Mitochondria are the remnants of the ancient endosymbiont bacteria that together with a cell related to the asgard archaea formed the original ur-eukaryote (1). Mitochondria are however best known as the powerhouses responsible for energy production in eukaryotic cells, and they play a pivotal role in maintaining cellular and organismal health, and metabolic homeostasis. Any compromise in their functionality can have far-reaching consequences.
Notably, dysfunctional mitochondria are frequently associated with the excessive generation of intracellular reactive oxygen species (ROS), leading to a state of enhanced oxidative stress. This oxidative stress is not only detrimental to the mitochondria themselves, but also initiates destructive cascades, impacting the entirety of the cellular machinery and creating pathological feedback loops, such as the immunogenic cell death via ferroptosis (2); further exacerbating the tissue damage inflicted. Indeed, mitochondrial ROS-induced damage, cell death, and subsequent immunogenicity are significant drivers onto several autoimmune diseases and could thus potentially be a therapeutic target, for example in rheumatoid arthritis as discussed by Jing et al. By contrast, increased resistance to oxidative stress due to overexpression of glucose 6-phosphate dehydrogenase has been implicated in the causation and flare of rheumatoid arthritis (3). Alternatively, mitochondrial oxidative stress is a driver of lupus (4), which is responsive to treatment with antioxidants, such as acetylcysteine (5).
Dysfunctional mitochondria can release mitochondrial-derived nucleic acids into both the intracellular and extracellular milieu. This phenomenon holds the potential to amplify pro-inflammatory type I interferon (IFN) responses, a prominent feature in certain autoimmune disorders (6) — so-called interferonopathies. Furthermore, these malfunctioning mitochondria may serve as a source of modified self-antigens, commonly referred to as autoantigens, which can contribute to the development of autoimmune conditions. In addition, they can release danger-associated molecular patterns (DAMPs), further intensifying the inflammatory response. Examples of these mitochondria-derived DAMPs (mtDAMPs) have been discussed in this Research Topic as a hypothetical driver of Kawasaki disease by Beckley et al. and how mtDAMPs can induce systemic inflammation after local tissue damage were reviewed in this Research Topic by Ye et al.
Notably, malfunctioning mitochondria within crucial immune cells may disrupt the establishment of regulatory networks that are essential for preventing, attenuating, or controlling autoimmune conditions and inflammatory processes. Moreover, metabolic disturbances in non-immune cells can indirectly result in an immune cell phenotype. For example, as demonstrated by a transcriptomic analysis on polycystic ovary syndrome (PCOS) by Chen et al., disturbances in primary metabolism in hormone-producing cells can indirectly result in immune cell activation. Therefore, understanding the intricate interplay between mitochondrial dysfunction and the initiation and perpetuation of inflammation and autoimmunity is of paramount importance.
Author contributions
JS: Writing – original draft, Writing – review & editing. LB: Writing – review & editing. AP: Writing – review & editing.
Funding
The author(s) declare financial support was received for the research, authorship, and/or publication of this article. AP was supported in part by grants AR076092, AI072648 and AI122176 from the National Institutes of Health and the Phillips Lupus and Autoimmunity Center of Excellence. JS was supported in part by a VIB Grand Challenges grant (GC01-C01), the Fund for Scientific Research Flanders (FWO; G021119N) and Ghent University Concerted Research Actions (GOA; 01G00419).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
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References
1. Zaremba-Niedzwiedzka K, Caceres EF, Saw JH, Bäckström D, Juzokaite L, Vancaester E, et al. Asgard archaea illuminate the origin of eukaryotic cellular complexity. Nature (2017) 541:353–8. doi: 10.1038/nature21031
2. Shen L, Wang X, Zhai C, Chen Y. Ferroptosis: A potential therapeutic target in autoimmune disease (Review). Exp Ther Med (2023) 26:368. doi: 10.3892/etm.2023.12067
3. Yang Z, Shen Y, Oishi H, Matteson EL, Tian L, Goronzy JJ, et al. Restoring oxidant signaling suppresses proarthritogenic T cell effector functions in rheumatoid arthritis. Sci Transl Med (2016) 8:331ra38. doi: 10.1126/scitranslmed.aad7151
4. Doherty E, Oaks Z, Perl A. Increased mitochondrial electron transport chain activity at complex I is regulated by N-acetylcysteine in lymphocytes of patients with systemic lupus erythematosus. Antioxid Redox Signal (2014) 21:56–65. doi: 10.1089/ars.2013.5702
5. Lai Z-W, Hanczko R, Bonilla E, Caza TN, Clair B, Bartos A, et al. N-acetylcysteine reduces disease activity by blocking mammalian target of rapamycin in T cells from systemic lupus erythematosus patients: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum (2012) 64:2937–46. doi: 10.1002/art.34502
Keywords: inflammation, mitochondria, autoimmune diseases, ferroptosis, interferonopathy, metabolism, ROS - reactive oxygen species, DAMP (damage-associated molecular pattern)
Citation: Staal J, Blanco LP and Perl A (2023) Editorial: Mitochondrial dysfunction in inflammation and autoimmunity. Front. Immunol. 14:1304315. doi: 10.3389/fimmu.2023.1304315
Received: 29 September 2023; Accepted: 29 September 2023;
Published: 04 October 2023.
Edited and Reviewed by:
Pietro Ghezzi, University of Urbino Carlo Bo, ItalyCopyright © 2023 Staal, Blanco and Perl. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Jens Staal, amVucy5zdGFhbEBpcmMudmliLXVnZW50LmJl