Mills, E. L. et al. Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell 167, 457–470.e13 (2016).
Mills, E. L. et al. Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature 556, 113–117 (2018).
Tannahill, G. M. et al. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature 496, 238–242 (2013).
Lampropoulou, V. et al. Itaconate links inhibition of succinate dehydrogenase with macrophage metabolic remodeling and regulation of inflammation. Cell Metab. 24, 158–166 (2016).
Jha, A. K. et al. Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity 42, 419–430 (2015).
Billingham, L. K. et al. Mitochondrial electron transport chain is necessary for NLRP3 inflammasome activation. Nat. Immunol. 23, 692–704 (2022).
Mills, E. L., Kelly, B. & O’Neill, L. A. J. Mitochondria are the powerhouses of immunity. Nat. Immunol. 18, 488–498 (2017).
Adam, J. et al. Renal cyst formation in Fh1-deficient mice is independent of the Hif/Phd pathway: roles for fumarate in KEAP1 succination and Nrf2 signaling. Cancer Cell 20, 524–537 (2011).
Kornberg, M. D. et al. Dimethyl fumarate targets GAPDH and aerobic glycolysis to modulate immunity. Science 360, 449–453 (2018).
Humphries, F. et al. Succination inactivates gasdermin D and blocks pyroptosis. Science 369, 1633–1637 (2020).
Williams, N. C. et al. Signaling metabolite L-2-hydroxyglutarate activates the transcription factor HIF-1α in lipopolysaccharide-activated macrophages. J. Biol. Chem. 298, 101501 (2021).
Cordes, T. et al. Immunoresponsive gene 1 and itaconate inhibit succinate dehydrogenase to modulate intracellular succinate levels. J. Biol. Chem. 291, 14274–14284 (2016).
Sass, E., Blachinsky, E., Karniely, S. & Pines, O. Mitochondrial and cytosolic isoforms of yeast fumarase are derivatives of a single translation product and have identical amino termini. J. Biol. Chem. 276, 46111–46117 (2001).
Adam, J. et al. A role for cytosolic fumarate hydratase in urea cycle metabolism and renal neoplasia. Cell Rep. 3, 1440–1448 (2013).
Takeuchi, T., Schumacker, P. T. & Kozmin, S. A. Identification of fumarate hydratase inhibitors with nutrient-dependent cytotoxicity. J. Am. Chem. Soc. 137, 564–567 (2015).
Ryan, D. G. et al. Disruption of the TCA cycle reveals an ATF4-dependent integration of redox and amino acid metabolism. eLife 10, e72593 (2021).
Hayashi, G. et al. Dimethyl fumarate mediates Nrf2-dependent mitochondrial biogenesis in mice and humans. Hum. Mol. Genet. 26, 2864–2873 (2017).
Sciacovelli, M. et al. Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition. Nature 537, 544–547 (2016).
Wang, Y. P. et al. Malic enzyme 2 connects the Krebs cycle intermediate fumarate to mitochondrial biogenesis. Cell Metab. 33, 1027–1041 e1028 (2021).
Liao, S. T. et al. 4-Octyl itaconate inhibits aerobic glycolysis by targeting GAPDH to exert anti-inflammatory effects. Nat. Commun. 10, 5091 (2019).
Crooks, D. R. et al. Mitochondrial DNA alterations underlie an irreversible shift to aerobic glycolysis in fumarate hydratase-deficient renal cancer. Sci. Signal. 14, eabc4436 (2021).
Blatnik, M., Frizzell, N., Thorpe, S. R. & Baynes, J. W. Inactivation of glyceraldehyde-3-phosphate dehydrogenase by fumarate in diabetes: formation of S-(2-succinyl)cysteine, a novel chemical modification of protein and possible biomarker of mitochondrial stress. Diabetes 57, 41–49 (2008).
Tyrakis, P. A. et al. Fumarate hydratase loss causes combined respiratory chain defects. Cell Rep. 21, 1036–1047 (2017).
Ternette, N. et al. Inhibition of mitochondrial aconitase by succination in fumarate hydratase deficiency. Cell Rep. 3, 689–700 (2013).
Sullivan, L. B. et al. The proto-oncometabolite fumarate binds glutathione to amplify ROS-dependent signaling. Mol. Cell 51, 236–248 (2013).
Zheng, L. et al. Fumarate induces redox-dependent senescence by modifying glutathione metabolism. Nat. Commun. 6, 6001 (2015).
Bambouskova, M. et al. Electrophilic properties of itaconate and derivatives regulate the IκBζ–ATF3 inflammatory axis. Nature 556, 501–504 (2018).
Raimundo, N., Vanharanta, S., Aaltonen, L. A., Hovatta, I. & Suomalainen, A. Downregulation of SRF–FOS–JUNB pathway in fumarate hydratase deficiency and in uterine leiomyomas. Oncogene 28, 1261–1273 (2009).
Hu, X. et al. IFN-γ suppresses IL-10 production and synergizes with TLR2 by regulating GSK3 and CREB/AP-1 proteins. Immunity 24, 563–574 (2006).
Angel, P., Hattori, K., Smeal, T. & Karin, M. The jun proto-oncogene is positively autoregulated by its product, Jun/AP-1. Cell 55, 875–885 (1988).
Dickinson, S. E. et al. Inhibition of activator protein-1 by sulforaphane involves interaction with cysteine in the cFos DNA-binding domain: implications for chemoprevention of UVB-induced skin cancer. Cancer Res. 69, 7103–7110 (2009).
de Waal Malefyt, R., Abrams, J., Bennett, B., Figdor, C. G. & de Vries, J. E. Interleukin 10 (IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J. Exp. Med. 174, 1209–1220 (1991).
Luan, H. H. et al. GDF15 is an inflammation-induced central mediator of tissue tolerance. Cell 178, 1231–1244.e11 (2019).
Day, E. A. et al. Metformin-induced increases in GDF15 are important for suppressing appetite and promoting weight loss. Nat. Metab. 1, 1202–1208 (2019).
Coll, A. P. et al. GDF15 mediates the effects of metformin on body weight and energy balance. Nature 578, 444–448 (2020).
Wang, Y. et al. SLC25A39 is necessary for mitochondrial glutathione import in mammalian cells. Nature 599, 136–140 (2021).
Weng, J. H. et al. Colchicine acts selectively in the liver to induce hepatokines that inhibit myeloid cell activation. Nat. Metab. 3, 513–522 (2021).
Eisenstein, A. et al. Activation of the transcription factor NRF2 mediates the anti-inflammatory properties of a subset of over-the-counter and prescription NSAIDs. Immunity 55, 1082–1095.e5 (2022).
Asadullah, K. et al. Influence of monomethylfumarate on monocytic cytokine formation—explanation for adverse and therapeutic effects in psoriasis? Arch. Dermatol. Res. 289, 623–630 (1997).
Arts, R. J. et al. Glutaminolysis and fumarate accumulation integrate immunometabolic and epigenetic programs in trained immunity. Cell Metab. 24, 807–819 (2016).
Ryan, D. G. et al. Nrf2 activation reprograms macrophage intermediary metabolism and suppresses the type I interferon response. iScience 25, 103827 (2022).
Shanmugasundaram, K. et al. The oncometabolite fumarate promotes pseudohypoxia through noncanonical activation of NF-κB signaling. J. Biol. Chem. 289, 24691–24699 (2014).
West, A. P. et al. Mitochondrial DNA stress primes the antiviral innate immune response. Nature 520, 553–557 (2015).
Sliter, D. A. et al. Parkin and PINK1 mitigate STING-induced inflammation. Nature 561, 258–262 (2018).
McArthur, K. et al. BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis. Science 359, eaao6047 (2018).
Dang, E. V., McDonald, J. G., Russell, D. W. & Cyster, J. G. Oxysterol restraint of cholesterol synthesis prevents AIM2 inflammasome activation. Cell 171, 1057–1071.e11 (2017).
Haag, S. M. et al. Targeting STING with covalent small-molecule inhibitors. Nature 559, 269–273 (2018).
Stunz, L. L. et al. Inhibitory oligonucleotides specifically block effects of stimulatory CpG oligonucleotides in B cells. Eur. J. Immunol. 32, 1212–1222 (2002).
Prantner, D. et al. 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) activates stimulator of interferon gene (STING)-dependent innate immune pathways and is regulated by mitochondrial membrane potential. J. Biol. Chem. 287, 39776–39788 (2012).
Dhir, A. et al. Mitochondrial double-stranded RNA triggers antiviral signalling in humans. Nature 560, 238–242 (2018).
Tigano, M., Vargas, D. C., Tremblay-Belzile, S., Fu, Y. & Sfeir, A. Nuclear sensing of breaks in mitochondrial DNA enhances immune surveillance. Nature 591, 477–481 (2021).
Kariko, K., Buckstein, M., Ni, H. & Weissman, D. Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. Immunity 23, 165–175 (2005).
Rai, P. et al. IRGM1 links mitochondrial quality control to autoimmunity. Nat. Immunol. 22, 312–321 (2021).
Kruger, A. et al. Human TLR8 senses UR/URR motifs in bacterial and mitochondrial RNA. EMBO Rep. 16, 1656–1663 (2015).
Pichlmair, A. et al. RIG-I-mediated antiviral responses to single-stranded RNA bearing 5′-phosphates. Science 314, 997–1001 (2006).
Koshiba, T., Yasukawa, K., Yanagi, Y. & Kawabata, S. Mitochondrial membrane potential is required for MAVS-mediated antiviral signaling. Sci. Signal. 4, ra7 (2011).
Kim, S. et al. Mitochondrial double-stranded RNAs govern the stress response in chondrocytes to promote osteoarthritis development. Cell Rep. 40, 111178 (2022).
Rasa, S. M. M. et al. Inflammaging is driven by upregulation of innate immune receptors and systemic interferon signaling and is ameliorated by dietary restriction. Cell Rep. 39, 111017 (2022).
Buskiewicz, I. A. et al. Reactive oxygen species induce virus-independent MAVS oligomerization in systemic lupus erythematosus. Sci. Signal. 9, ra115 (2016).
Ruiz-Limon, P. et al. Atherosclerosis and cardiovascular disease in systemic lupus erythematosus: effects of in vivo statin treatment. Ann. Rheum. Dis. 74, 1450–1458 (2015).
Davis, P., Cunnington, P. & Hughes, G. R. Double-stranded RNA antibodies in systemic lupus erythematosus. Ann. Rheum. Dis. 34, 239–243 (1975).
Caielli, S. et al. Oxidized mitochondrial nucleoids released by neutrophils drive type I interferon production in human lupus. J. Exp. Med. 213, 697–713 (2016).
Sarkar, P. et al. Reduced expression of mitochondrial fumarate hydratase in progressive multiple sclerosis contributes to impaired in vitro mesenchymal stromal cell-mediated neuroprotection. Mult. Scler. 28, 1179–1188 (2022).
Zecchini, V. et al. Fumarate induces vesicular release of mtDNA to drive innate immunity. Nature https://doi.org/10.1038/s41586-023-05770-w (2023).
Li, Q. et al. RNA editing underlies genetic risk of common inflammatory diseases. Nature 608, 569–577 (2022).
Pang, Z. et al. MetaboAnalyst 5.0: narrowing the gap between raw spectra and functional insights. Nucleic Acids Res. 49, W388–W396 (2021).
Anders, S. & Huber, W. Differential expression analysis for sequence count data. Genome Biol. 11, R106 (2010).
Shah, A. D., Goode, R. J. A., Huang, C., Powell, D. R. & Schittenhelm, R. B. LFQ-Analyst: an easy-to-use interactive web platform to analyze and visualize label-free proteomics data preprocessed with MaxQuant. J. Proteome Res. 19, 204–211 (2020).
Kuleshov, M. V. et al. Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res. 44, W90–W97 (2016).
Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005).
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