The role of mitochondria in rheumatic diseases

Oxidation of mitochondrial epitopes during apoptosis might form neoantigens recognized by anti-mitochondrial antibodies.

“The oxidation of mitochondrial epitopes during apoptosis might lead to formation of neoantigens that are recognized by anti-mitochondrial antibodies228.”

• cites [228] Odin, J. A., Huebert, R. C., Casciola-Rosen, L., LaRusso, N. F. & Rosen, A. Bcl-2-dependent oxidation of pyruvate dehydrogenase-E2, a primary biliary cirrhosis autoantigen, during apoptosis. J. Clin. Invest. 108, 223–232 (2001). sourceDisputed

  The Discussion (page not provided) says that oxidation of PDC-E2 during apoptosis causes loss of the epitope recognized by primary biliary cirrhosis patient autoantibodies. It proposes that the reduced, unmodified form—not the oxidized form—activates PDC-E2-specific B cells. Although the Introduction raises the general possibility of apoptotic neoantigens, the paper's finding runs contrary to the claimed antibody recognition of oxidized mitochondrial epitopes. (LLM, conf=0.88)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

In some European populations, individuals with mitochondrial haplogroups J and T have a decreased risk of developing osteoarthritis and psoriatic arthritis.

“In some European populations, individuals harbouring the mitochondrial haplogroups J and T have a decreased risk of developing osteoarthritis and psoriatic arthritis compared with the rest of the population36,37”

• cites [36] Soto-Hermida, A. et al. mtDNA haplogroups and osteoarthritis in different geographic populations. Mitochondrion 15, 18–23 (2014). sourcePartly supported

  The Discussion reports a protective association between haplogroup J and osteoarthritis in Spanish cohorts; Results §3.2 reports a lower probability of osteoarthritis for haplogroup T in the UK cohort. The paper does not report a decreased risk of psoriatic arthritis, so that part of the claim is unsupported. (LLM, conf=0.89)

  Experimental — accuracy not yet measured
• cites [37] Coto-Segura, P. et al. Common European mitochondrial haplogroups in the risk for psoriasis and psoriatic arthritis. Genet. Test. Mol. Biomark. 16, 621–623 (2012). sourceNot checked — no full text of the source

Some non-synonymous MT-ND1 changes generate predicted epitopes for rheumatoid arthritis-predisposing MHC class II alleles, suggesting a role for these mutations in rheumatoid arthritis pathogenesis.

“Some of the non-synonymous changes within MT-ND1 generated predicted epitopes for RA-predisposing MHC class II alleles (HLA-DRβ1*0101 and HLA-DRβ1*0401), suggesting a role for these mutations in RA pathogenesis44”

• cites [44] Da Sylva, T. R., Connor, A., Mburu, Y., Keystone, E. & Wu, G. E. Somatic mutations in the mitochondria of rheumatoid arthritis synoviocytes. Arthritis Res. Ther. 7, R844–R851 (2005). sourceSupported

Mitochondria express biomolecules resembling prokaryotic molecules, such as cardiolipin, double-stranded hypomethylated DNA and N-formylated peptides.

“these organelles express biomolecules that resemble those expressed by prokaryotes, such as cardiolipin, double-stranded-hypomethylated DNA and N-formylated peptides12,13”

• cites [12] Krysko, D. V. et al. Emerging role of damage-associated molecular patterns derived from mitochondria in inflammation. Trends Immunol. 32, 157–164 (2011). sourceNot checked — no full text of the source
• cites [13] Zhang, Q. et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 464, 104–107 (2010). sourcePartly supported

  The paper’s Abstract says mitochondrial DNA resembles bacterial DNA in having nonmethylated CpG motifs and identifies mitochondrial formyl peptides as bacterial-like molecular signatures. It does not identify cardiolipin among those signatures or specify that the DNA is double-stranded; those details are not supported by our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

One study reported an increased frequency of mitochondrial DNA somatic mutations in synoviocytes from patients with rheumatoid arthritis compared with synoviocytes from patients with osteoarthritis.

“one study reported an increase in the frequency of mtDNA somatic mutations in synoviocytes from patients with RA compared with synoviocytes from patients with OA44”

• cites [44] Da Sylva, T. R., Connor, A., Mburu, Y., Keystone, E. & Wu, G. E. Somatic mutations in the mitochondria of rheumatoid arthritis synoviocytes. Arthritis Res. Ther. 7, R844–R851 (2005). sourceSupported

Mitochondrial haplogroups carrying pathogenic SNPs can contribute to metabolic, late-onset neurodegenerative and autoimmune diseases.

“MtDNA haplogroups with pathogenic SNPs can contribute to metabolic, late-onset neurodegenerative diseases and autoimmune diseases through various mechanisms32,33”

• cites [32] Schon, E. A., DiMauro, S. & Hirano, M. Human mitochondrial DNA: roles of inherited and somatic mutations. Nat. Rev. Genet. 13, 878–890 (2012). sourcePartly supported

  The 'Mitochondrial haplotypes as modifiers' section says pathogenic mtDNA mutations can cause diabetes and describes a haplogroup modifying the effects of an optic-neuropathy mutation. But 'Susceptibility to complex disorders' calls links between haplogroups and metabolic or neurodegenerative disorders highly controversial and concludes that the evidence is too weak to establish a contribution. The paper mentions an autoimmune response to mitochondrial dysfunction, not autoimmune disease caused by haplogroups carrying pathogenic SNPs. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [33] Sun, D., Wei, Y., Zheng, H. X., Jin, L. & Wang, J. Contribution of mitochondrial DNA variation to chronic disease in East Asian populations. Front. Mol. Biosci. 6, 128 (2019). sourcePartly supported

  The Introduction and the sections on endocrine and nervous-system diseases (page numbers unavailable) link mtDNA variants and haplogroups to metabolic disorders and neurodegenerative diseases. The paper does not establish a link to autoimmune diseases, and its Conclusions say the specific disease mechanisms require further investigation. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

Individuals with D-loop polycytidine alterations have lower mitochondrial DNA copy numbers than individuals with intact D-loops.

“Individuals with D-loop polymorphisms (namely, polycytidine (polyC) alterations) have lower mtDNA copy numbers than individuals with intact D-loops38,39”

• cites [38] Lee, H. T. et al. Leukocyte mitochondrial DNA alteration in systemic lupus erythematosus and its relevance to the susceptibility to lupus nephritis. Int. J. Mol. Sci. 13, 8853–8868 (2012). sourcePartly supported

  Results and Discussion (§2.2–2.3; page unavailable) report that declining leukocyte mtDNA copy number with increasing SLE disease activity was more pronounced in patients with D310 heteroplasmy. The paper does not establish the broader claim that individuals with polycytidine alterations have lower copy numbers than individuals with intact D-loops; its reported comparison concerns disease activity within the studied SLE patients. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [39] Liou, C. W. et al. Association between a common mitochondrial DNA D-loop polycytosine variant and alteration of mitochondrial copy number in human peripheral blood cells. J. Med. Genet. 47, 723–728 (2010). sourceNot checked — no full text of the source

Some D-loop polyC variants, including nt16189 T>C and D310 alterations, are associated with susceptibility to SLE and disease severity.

“Some D-loop polyC variants are associated with susceptibility to SLE and disease severity, including alterations at nt16189 (a T > C polymorphism) and in the D310 region38,40”

• cites [38] Lee, H. T. et al. Leukocyte mitochondrial DNA alteration in systemic lupus erythematosus and its relevance to the susceptibility to lupus nephritis. Int. J. Mol. Sci. 13, 8853–8868 (2012). sourceSupported
• cites [40] Jonsen, A. et al. Mitochondrial DNA polymorphisms are associated with susceptibility and phenotype of systemic lupus erythematosus. Lupus 18, 309–312 (2009). sourceNot checked — no full text of the source

These oxidative events can generate neoantigens that the adaptive immune system may recognize as exogenous threats.

“These events can lead to the generation of neoantigens that could be recognized as exogenous threats by the adaptive immune system68”

• cites [68] Perl, A. Oxidative stress in the pathology and treatment of systemic lupus erythematosus. Nat. Rev. Rheumatol. 9, 674–686 (2013). sourceSupported

In a chronic graft-versus-host-disease model of SLE, C1q but not C3 can modulate mitochondrial metabolism in CD8+ T cells to limit self-reactive responses.

“Investigations of C1q or C3 deficiency in a chronic graft-versus-host-disease model of SLE indicate that C1q, but not C3, could modulate mitochondrial metabolism in CD8+ T cells to limit self-reactive responses81”

• cites [81] Ling, G. S. et al. C1q restrains autoimmunity and viral infection by regulating CD8+ T cell metabolism. Science 360, 558–563 (2018). sourceSupported

T cell activation upregulates glucose transporter 1 through T cell receptor, CD28 and PI3K-Akt-mTOR signalling, increasing aerobic glycolysis.

“signalling pathways involving the T cell receptor (TCR), CD28 and the PI3K–Akt–mTOR axis upregulate the expression of glucose transporter 1 (GLUT1), increasing the rate of aerobic glycolysis71,72”

• cites [71] van der Windt, G. J. & Pearce, E. L. Metabolic switching and fuel choice during T-cell differentiation and memory development. Immunol. Rev. 249, 27–42 (2012). sourcePartly supported

  The “Glucose and proliferating T cells” section says TCR stimulation moves Glut1 to the cell surface, while CD28 signals increase its expression and surface localization. The “Conventional view of T-cell metabolism” section links CD28–PI3K–AKT and mTOR signaling to increased glycolysis. It does not say that TCR signaling increases Glut1 expression, or specifically that mTOR increases Glut1 expression; page numbers were not supplied. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [72] Frauwirth, K. A. et al. The CD28 signaling pathway regulates glucose metabolism. Immunity 16, 769–777 (2002). sourceNot checked — no full text of the source

Dietary biomolecules can modulate mitochondrial activity in pathways involved in energy supply, mitochondrial dynamics and mitochondrial reactive oxygen species production.

“Biomolecules provided by the diet are also able to modulate mitochondrial activity in various metabolic pathways, such as those involved in energy supply, mitochondrial dynamics and mtROS production84”

• cites [84] Oaks, Z. & Perl, A. Metabolic control of the epigenome in systemic lupus erythematosus. Autoimmunity 47, 256–264 (2014). sourcePartly supported

  The Abstract and Introduction link diet-derived metabolites to metabolic pathways and identify mitochondria as sources of ATP and reactive oxygen intermediates. They do not establish that dietary biomolecules modulate mitochondrial dynamics or mitochondrial reactive oxygen species production; searches for those links found no supporting passage. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Short-lived effector cells expanded in the absence of C1q contribute to self-reactive responses and tissue inflammation.

“short-lived effector cells, expanded in the absence of C1q, contribute to self-reactive responses and tissue inflammation”

• cites [81] Ling, G. S. et al. C1q restrains autoimmunity and viral infection by regulating CD8+ T cell metabolism. Science 360, 558–563 (2018). sourceSupported

T helper 10 cells might contribute to SLE pathogenesis and end organ damage by supporting extrafollicular humoral responses.

“These cells might contribute to SLE pathogenesis and end organ damage via supporting extrafollicular humoral responses75”

• cites [75] Caielli, S. et al. A CD4+ T cell population expanded in lupus blood provides B cell help through interleukin-10 and succinate. Nat. Med. 25, 75–81 (2019). sourceSupported

Mitochondrial dysfunction in rodent models of arthritis can be reduced by treatment with statins or antioxidants such as coenzyme Q10 or omega-3.

“mitochondrial dysfunction in rodent models of arthritis could be reduced via treatment with statins or antioxidants (for example, Coenzyme Q10 or omega-3)87,88”

• cites [87] Farnaghi, S. et al. Protective effects of mitochondria-targeted antioxidants and statins on cholesterol-induced osteoarthritis. FASEB J. 31, 356–367 (2017). sourceNot checked — no full text of the source
• cites [88] Kucharská, J. et al. Treatment with coenzyme Q10, ω-3-polyunsaturated fatty acids and their combination improved bioenergetics and levels of coenzyme Q9 and Q10 in skeletal muscle mitochondria in experimental model of arthritis. Physiol. Res. 70, 723–733 (2021). sourcePartly supported

  The Summary (p. 1) and Discussion (p. 7) report that coenzyme Q10 and omega-3 fatty acids improved skeletal-muscle mitochondrial function in arthritic rats. The cited paper does not support the sentence’s statin-treatment claim. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

In mice, C1qBP expression is higher in effector CD8+ T cells than in naive cells.

“In mice, the expression of C1qBP is higher in effector CD8+ T cells than in naive cells”

• cites [81] Ling, G. S. et al. C1q restrains autoimmunity and viral infection by regulating CD8+ T cell metabolism. Science 360, 558–563 (2018). sourcePartly supported

  The passage discussing Fig. S11B–C reports increased p32/gC1qR expression on activated mouse CD8+ T cells. It does not explicitly compare effector CD8+ T cells with naïve cells, so the claim is more specific than the reported finding. (LLM, conf=0.78)

  Experimental — accuracy not yet measured

In the blood of patients with SLE, concomitant oxidation of mitochondrial DNA and Notch pathway signalling induce expansion of a unique population of CD4+ T cells known as T helper 10 cells.

“In the blood of patients with SLE, concomitant oxidation of mtDNA and signalling through the Notch pathway induce the expansion of a unique population of CD4+ T cells (CXCR5−CXCR3+PD1hiCD4+ T cells, known as T helper 10 (TH10) cells)75,76”

• cites [75] Caielli, S. et al. A CD4+ T cell population expanded in lupus blood provides B cell help through interleukin-10 and succinate. Nat. Med. 25, 75–81 (2019). sourcePartly supported

  The paper reports that CXCR5− CXCR3+ PD1hi CD4+ T cells are expanded in SLE blood and that similar cells can be generated in vitro using plasmacytoid dendritic cells activated by oxidized mtDNA (Abstract; passage [2]). It does not establish that oxidized mtDNA and Notch signalling act together to induce their expansion in patients, and our copy does not identify the cells as TH10 (searched: Notch, TH10). (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [76] Caielli, S., Banchereau, J. & Pascual, V. Dissecting the mechanisms responsible for the generation of regulatory versus pathogenic human CD4+ T cells by TLR9-activated plasmacytoid dendritic cells. J. Immunol. 204, 230.233–230.233 (2020). sourceNot checked — no full text of the source

C1q binding protein is considered a modulator of mitochondrial activity through its ability to regulate protein translation within the organelle.

“The C1q binding protein (C1qBP, also known as p32 or gC1qR) is considered a modulator of mitochondrial activity through its ability to regulate protein translation within the organelle82”

• cites [82] Yagi, M. et al. p32/gC1qR is indispensable for fetal development and mitochondrial translation: importance of its RNA-binding ability. Nucleic Acids Res. 40, 9717–9737 (2012). sourceSupported

Confocal microscopy analyses indicate that C1q and C1qBP co-localize in mitochondria.

“confocal microscopy analyses indicate that C1q and C1qBP co-localized in mitochondria”

• cites [81] Ling, G. S. et al. C1q restrains autoimmunity and viral infection by regulating CD8+ T cell metabolism. Science 360, 558–563 (2018). sourceSupported
• cites [83] Weyand, C. M. & Goronzy, J. J. A mitochondrial checkpoint in autoimmune disease. Cell Metab. 28, 185–186 (2018). sourcePartly supported

  The passage labeled Abstract (page unavailable) says that C1q bound to its receptor p32 and translocated to mitochondria, supporting an association there. It does not identify p32 as C1qBP or report confocal microscopy showing co-localization, so the specific imaging claim is not established by this copy. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

The existence of redundant mechanisms for clearing apoptotic debris suggests that C1q has an alternative function in maintaining self-tolerance in SLE.

“the existence of redundant mechanisms in clearing apoptotic debris, including those mediated by C3 and complement activation independent of C1q79,80, suggest that C1q has an alternative function in maintaining self-tolerance in SLE”

• cites [79] Martin, M. & Blom, A. M. Complement in removal of the dead — balancing inflammation. Immunol. Rev. 274, 218–232 (2016). sourceNot checked — no full text of the source
• cites [80] Thielens, N. M., Tedesco, F., Bohlson, S. S., Gaboriaud, C. & Tenner, A. J. C1q: a fresh look upon an old molecule. Mol. Immunol. 89, 73–83 (2017). sourcePartly supported

  Section 2.4 (page unavailable) describes an immunoregulatory role for C1q beyond debris clearance: it promotes anti-inflammatory responses and limits responses to self-antigens, consistent with maintaining self-tolerance. But the paper does not establish the claimed redundancy of apoptotic-debris clearance mechanisms; it instead describes a predominant role for C1q over C1 activation and C3b deposition in apoptotic-cell clearance and immunosuppression. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Numerous metabolic pathways are downregulated in CD8+ T cells from patients with SLE.

“numerous metabolic pathways are downregulated in CD8+ T cells in patients with SLE”

• cites [74] Buang, N. et al. Type I interferons affect the metabolic fitness of CD8+ T cells from patients with systemic lupus erythematosus. Nat. Commun. 12, 1980 (2021). sourcePartly supported

  The Results section, “Downregulation of OXPHOS genes in patients with high expression of ISGs” (page unavailable), reports downregulation of pathways involved in the TCA cycle, electron transport chain, and ATP synthesis, more pronounced in CD8+ T cells. The comparison is specifically between SLE patients with high and lower interferon signatures; the claim omits that restriction and reads as applying to patients with SLE generally. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

A genetic variant of F0F1-ATP synthase is associated with the development of SLE.

“a genetic variant of F0F1–ATP synthase is associated with the development of SLE35”

• cites [35] Vyshkina, T. et al. Association of common mitochondrial DNA variants with multiple sclerosis and systemic lupus erythematosus. Clin. Immunol. 129, 31–35 (2008). sourceSupported

Metabolic aberrations induced by mitochondrial abnormalities are linked to self-reactive and inflammatory phenotypes in autoimmune conditions including SLE and rheumatoid arthritis.

“In various cell types, metabolic aberrations induced by mitochondrial abnormalities are linked to self-reactive and inflammatory phenotypes in autoimmune conditions, including SLE and RA68,69”

• cites [68] Perl, A. Oxidative stress in the pathology and treatment of systemic lupus erythematosus. Nat. Rev. Rheumatol. 9, 674–686 (2013). sourcePartly supported

  The sections on diminished antioxidant defences and oxidative autoantigenesis link mitochondrial dysfunction and oxidative stress in SLE to autoreactivity and inflammation. The section on increased mitochondrial ROI production also associates a mitochondrial-protein variant with predisposition to RA, but it does not establish the claimed link to self-reactive or inflammatory phenotypes in RA. Page numbers are unavailable in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [69] Lee, H. T. et al. The pathogenesis of systemic lupus erythematosus — from the viewpoint of oxidative stress and mitochondrial dysfunction. Mitochondrion 30, 1–7 (2016). sourceNot checked — no full text of the source

SLE CD8+ T cells express higher levels of interferon-stimulated genes than healthy individuals.

“these cells express higher levels of interferon-stimulated genes compared with those of healthy individuals”

• cites [74] Buang, N. et al. Type I interferons affect the metabolic fitness of CD8+ T cells from patients with systemic lupus erythematosus. Nat. Commun. 12, 1980 (2021). sourceSupported

mtDNA extrusion can occur through NET formation.

“Extrusion of mtDNA can also occur through NET formation57.”

• cites [57] Lood, C. et al. Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat. Med. 22, 146–153 (2016). sourceSupported

In homeostasis, RAB4A promotes lysosomal degradation of DRP1, inhibiting mitochondrial fission and mitophagy.

“In homeostasis, RAB4A promotes lysosomal degradation of DRP1, subsequently inhibiting mitochondrial fission and mitophagy”

• cites [116] Caza, T. N. et al. HRES-1/Rab4-mediated depletion of Drp1 impairs mitochondrial homeostasis and represents a target for treatment in SLE. Ann. Rheum. Dis. 73, 1888–1897 (2014). sourcePartly supported

  The Results section ('HRES-1/Rab4 promotes the lysosomal degradation of Drp1'; page not provided) reports that HRES-1/Rab4 overexpression depleted Drp1, with evidence implicating lysosomal degradation. The Results and Discussion link HRES-1/Rab4 to inhibited mitophagy, while the Introduction identifies Drp1 as initiating mitochondrial fission. The paper establishes these effects chiefly in overexpression experiments, not specifically as a process occurring 'in homeostasis.' (LLM, conf=0.84)

  Experimental — accuracy not yet measured

In neutrophils activated by immune complexes containing U1 snRNPs, mitochondria produce excessive ROS that supports NET formation and extrusion.

“Mechanistically, in neutrophils activated by immune complexes containing U1 small nuclear ribonucleoproteins (SnRNPs), mitochondria generate excessive amounts of ROS, which supports the formation and extrusion of NETs”

• cites [57] Lood, C. et al. Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat. Med. 22, 146–153 (2016). sourcePartly supported

  The Results section on RNP immune complex–mediated NETosis reports increased mitochondrial ROS after neutrophil activation and shows that inhibiting mitochondrial activity reduces NET formation. The Online methods describe the complexes as containing SmRNP antigen and anti-RNP antibodies, but our copy does not identify the antigen specifically as U1 snRNP. No page numbers are available in our copy. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

In the absence of active caspases, mitochondrial DNA released after mitochondrial outer membrane permeabilization triggers type I interferon responses in a cGAS-STING-dependent manner.

“In the absence of active caspases, mtDNA released following mitochondrial outer membrane permeabilization triggers type I interferon responses in a cGAS–STING-dependent manner143,144”

• cites [143] Rongvaux, A. et al. Apoptotic caspases prevent the induction of type I interferons by mitochondrial DNA. Cell 159, 1563–1577 (2014). sourceSupported
  Experimental — accuracy not yet measured
• cites [144] White, M. J. et al. Apoptotic caspases suppress mtDNA-induced STING-mediated type I IFN production. Cell 159, 1549–1562 (2014). sourceSupported
  Experimental — accuracy not yet measured

Abnormal retention of mitochondria in mature erythrocytes in patients with SLE is caused by a defective hypoxia-inducible factor-mediated metabolic switch that impairs activation of the ubiquitin-proteasome system necessary for mitophagy during erythroid maturation.

“Abnormal retention of mitochondria in mature erythrocytes in patients with SLE is caused by a defective hypoxia-inducible factor (HIF)-mediated metabolic switch that leads to impaired activation of the ubiquitin-proteasome system, necessary for the execution of mitophagy during human erythroid cell maturation”

• cites [119] Caielli, S. et al. Erythroid mitochondrial retention triggers myeloid-dependent type I interferon in human SLE. Cell 184, 4464–4479 e4419 (2021). sourceSupported

Mitochondrial DNA or mitochondrial RNA released into the cytosol through BAX-BAK macropores can activate cytosolic nucleic acid sensors independently of cell death, leading to type I interferon production.

“mtDNA or mtRNA released into the cytosol via BAX–BAK macropores can activate nucleic acid sensors in the cytosol145 independently of cell death130,146,147, ultimately leading to the production of type I interferon”

• cites [145] Todkar, K. et al. Selective packaging of mitochondrial proteins into extracellular vesicles prevents the release of mitochondrial DAMPs. Nat. Commun. 12, 1971 (2021). sourcePartly supported

  The Results section (‘Mitochondria, not EVs stimulate a strong IL6 response’; page unavailable) reports mitochondrial cargo in extracellular vesicles when cell death was kept below 5%, and an IP10 response to those vesicles. This supports an inflammatory response without substantial cell death, but the paper does not establish release of mtDNA or mtRNA into the cytosol through BAX–BAK macropores, activation of cytosolic nucleic-acid sensors, or resulting type I interferon production. (LLM, conf=0.79)

  Experimental — accuracy not yet measured
• cites [130] McArthur, K. et al. BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis. Science 359, eaao6047–eaao6047 (2018). sourceNot checked — no full text of the source
• cites [146] Aarreberg, L. D. et al. Interleukin-1β induces mtDNA release to activate innate immune signaling via cGAS-STING. Mol. Cell 74, 801–815.e6 (2019). sourcePartly supported

  The Results and Discussion report that IL-1β induces cytosolic mtDNA release without detectable cell death, followed by cGAS–STING signaling and IFNB1 induction (pages not provided). The paper does not establish release through BAX–BAK macropores or show that mtRNA drives this response; its Discussion says the mechanism of mtDNA release remains unknown. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [147] West, A. P. et al. Mitochondrial DNA stress primes the antiviral innate immune response. Nature 520, 553–557 (2015). sourceSupported

High interferon-stimulated gene signatures in patients with SLE are associated with the presence of mitochondria-containing erythrocytes and opsonizing antibodies.

“high interferon-stimulated gene signatures in patients with SLE are associated with the presence of mitochondria-containing erythrocytes and opsonizing antibodies119”

• cites [119] Caielli, S. et al. Erythroid mitochondrial retention triggers myeloid-dependent type I interferon in human SLE. Cell 184, 4464–4479 e4419 (2021). sourceSupported

Depleting BAX and BAK or inhibiting BAX oligomerization in these cells substantially reduces mtDSB-induced type I interferon response.

“Consistently, depletion of BAX and BAK proteins or inhibition of BAX oligomerization in these cells leads to a considerable decrease in mtDSB-induced type I interferon response.”

• cites [149] 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). sourceSupported

In peripheral blood mononuclear cells, the level of VDAC oligomers and cytosolic mitochondrial DNA is higher in patients with SLE than in healthy individuals.

“in peripheral blood mononuclear cells, the level of VDAC oligomers and cytosolic mtDNA is higher in patients with SLE than in healthy individuals”

• cites [148] Kim, J. et al. VDAC oligomers form mitochondrial pores to release mtDNA fragments and promote lupus-like disease. Science 366, 1531–1536 (2019). sourcePartly supported

  The passage discussing Fig. 4B reports more VDAC1 oligomers in PBMCs from patients with SLE than in healthy controls. It reports elevated cytosolic mtDNA in splenocytes from lupus-prone mice, not in human PBMCs; the latter part of the claim is therefore unsupported. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

mtDNA double-strand breaks caused by mitochondria-targeted nucleases or irradiation trigger cytosolic mtRNA leakage and RIGI-dependent interferon responses in human epithelial cells.

“Notably, mtDNA double-stranded breaks (mtDSBs) generated by mitochondria-targeted nucleases or irradiation can trigger cytosolic leakage of mtRNA and induce retinoic acid-inducible gene I (RIGI)-dependent interferon responses in human epithelial cells149.”

• cites [149] 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). sourceSupported

Selective packaging of mitochondrial proteins into mitochondria-derived vesicles prevents their release as mtDAMPs.

“This well-controlled process, involving the selective packaging of mitochondrial proteins in these vesicles, prevents their release as mtDAMPs by cells145”

• cites [145] Todkar, K. et al. Selective packaging of mitochondrial proteins into extracellular vesicles prevents the release of mitochondrial DAMPs. Nat. Commun. 12, 1971 (2021). sourceSupported

Phagocytosis of opsonized mitochondria-containing erythrocytes induces activation of the cGAS-STING pathway in macrophages and subsequent production of type I interferons.

“phagocytosis of opsonized mitochondria-containing erythrocytes induces activation of the DNA-sensing cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS–STING) pathway in macrophages and induces subsequent production of type I interferons119”

• cites [119] Caielli, S. et al. Erythroid mitochondrial retention triggers myeloid-dependent type I interferon in human SLE. Cell 184, 4464–4479 e4419 (2021). sourceSupported

Oxidized mtDNA released from SLE neutrophils can induce type I interferon production by plasmacytoid dendritic cells.

“Oxidized mtDNA released from neutrophils of patients with SLE can induce type I interferon production by plasmacytoid dendritic cells175”

• cites [175] 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). sourceSupported

Mitochondrial fMet peptide-mediated signalling is a potential therapeutic target for neutrophil-dominant inflammation in sterile inflammatory conditions such as RA.

“Furthermore, mitochondrial fMet peptide-mediated signalling is a potential therapeutic target for ameliorating neutrophil-dominant inflammation in sterile inflammatory conditions such as RA185.”

• cites [185] Duvvuri, B. et al. Mitochondrial N-formyl methionine peptides associate with disease activity as well as contribute to neutrophil activation in patients with rheumatoid arthritis. J. Autoimmun. 119, 102630 (2021). sourceSupported

Mitochondrial fMet peptides in RA plasma can support neutrophil activation in vitro via FPR1.

“Notably, mitochondrial fMet peptides circulating in the plasma of patients with RA can support neutrophil activation in vitro via FPR1 (as shown by FPR1 blockade experiments)185.”

• cites [185] Duvvuri, B. et al. Mitochondrial N-formyl methionine peptides associate with disease activity as well as contribute to neutrophil activation in patients with rheumatoid arthritis. J. Autoimmun. 119, 102630 (2021). sourceSupported

Increased mitochondrial fMet peptides in three independent RA cohorts correlate with circulating neutrophil activation markers (NETs, calprotectin, peroxidase) and inflammation markers (CRP, ESR).

“Specifically, increased levels of mitochondrial fMet peptides, as has been observed in three independent cohorts of patients with RA, correlate with circulating levels of neutrophil activation markers, including levels of NETs, calprotectin and peroxidase, as well as with markers of inflammation (such as C-reactive protein (CRP) level and erythrocyte sedimentation rate).”

• cites [185] Duvvuri, B. et al. Mitochondrial N-formyl methionine peptides associate with disease activity as well as contribute to neutrophil activation in patients with rheumatoid arthritis. J. Autoimmun. 119, 102630 (2021). sourceSupported

TNF and LPS may prime neutrophils by upregulating FPR1 expression.

“Some of the factors involved in priming these neutrophils could include TNF and LPS, which are known to upregulate the expression of FPR1 on neutrophils181–183.”

• cites [181] O’Flaherty, J. T., Rossi, A. G., Redman, J. F. & Jacobson, D. P. Tumor necrosis factor-α regulates expression of receptors for formyl-methionyl-leucyl-phenylalanine, leukotriene B4, and platelet-activating factor. Dissociation from priming in human polymorphonuclear neutrophils. J. Immunol. 147, 3842–3847 (1991). sourceNot checked — no full text of the source
• cites [182] Mandal, P., Novotny, M. & Hamilton, T. A. Lipopolysaccharide induces formyl peptide receptor 1 gene expression in macrophages and neutrophils via transcriptional and posttranscriptional mechanisms. J. Immunol. 175, 6085–6091 (2005). sourcePartly supported

  The section “LPS induces FPR1 mRNA via transcriptional and posttranscriptional mechanisms” (page not supplied) reports increased FPR1 mRNA in mouse neutrophils after LPS treatment. The cytokine experiments (Fig. 7; page not supplied) show that TNF-α increased FPR1 mRNA in macrophages, not neutrophils. The paper therefore supports the LPS portion but does not establish that TNF upregulates FPR1 in neutrophils or directly demonstrate neutrophil priming. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [183] Hirotani, T. et al. Regulation of lipopolysaccharide-inducible genes by MyD88 and Toll/IL-1 domain containing adaptor inducing IFN-β. Biochem. Biophys. Res. Commun. 328, 383–392 (2005). sourceNot checked — no full text of the source

In animal models of septic arthritis, bacteria-derived fMet peptides are virulence factors contributing to joint damage via neutrophil-mediated inflammation.

“Notably, data from animal models of septic arthritis have shown that bacteria-derived fMet peptides are virulence factors that contribute to joint damage via neutrophil-mediated inflammation in the joints184.”

• cites [184] Gjertsson, I., Jonsson, I. M., Peschel, A., Tarkowski, A. & Lindholm, C. Formylated peptides are important virulence factors in Staphylococcus aureus arthritis in mice. J. Infect. Dis. 205, 305–311 (2012). sourceSupported

Mitochondrial fMet peptides might be useful novel clinical biomarkers for disease activity and severity.

“Overall, these findings suggest that mitochondrial fMet peptides might be useful novel clinical biomarkers for measuring disease activity and disease severity.”

• cites [185] Duvvuri, B. et al. Mitochondrial N-formyl methionine peptides associate with disease activity as well as contribute to neutrophil activation in patients with rheumatoid arthritis. J. Autoimmun. 119, 102630 (2021). sourceSupported

Extracellular cytochrome c and oxidative stress markers in joints and connective tissues of psoriasis/psoriatic arthritis patients suggest mitochondrial dysfunction has a role in inflammatory arthritis.

“Additionally, the presence of extracellular cytochrome c and markers of oxidative stress in joints and connective tissues of patients with psoriasis or psoriatic arthritis suggests that mitochondrial dysfunction has a role in inflammatory arthritis210.”

• cites [210] Chimenti, M. S. et al. Potential role of cytochrome c and tryptase in psoriasis and psoriatic arthritis pathogenesis: focus on resistance to apoptosis and oxidative stress. Front. Immunol. https://doi.org/10.3389/fimmu.2018.02363 (2018). sourcePartly supported

  The Conclusions (page unavailable) say that oxidative stress and inflammation in psoriasis and psoriatic arthritis may lead to cytochrome c release into extracellular space. The section on oxidative stress in psoriatic arthritis reports mitochondrial DNA mutations and oxidative-stress findings in joint synovial cells. The paper does not establish that extracellular cytochrome c was detected in patients’ joints or connective tissues; it discusses circulating or serum cytochrome c instead. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

Mitochondria are the only cellular compartment that produces and sequesters endogenous N-formylated peptides.

“Thus, mitochondria are the only cellular compartment to produce and sequester endogenous N-formylated (fMet) peptides.”

• cites [176] Galper, J. B. Mitochondrial protein synthesis in HeLa cells. J. Cell Biol. 60, 755–763 (1974). sourcePartly supported

  The discussion (p. 762) says formylated f-Met-tRNA is found exclusively in mitochondria and that mitochondrial-specific protein synthesis is likely intramitochondrial. It does not establish that N-formylated peptides themselves are produced only there or sequestered there; those claims go beyond its findings in HeLa cells. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

Cardiolipin regulates mitochondrial fusion and fission.

“Cardiolipin is also involved in the regulation of mitochondrial fusion and fission191–193.”

• cites [191] Ban, T. et al. Molecular basis of selective mitochondrial fusion by heterotypic action between OPA1 and cardiolipin. Nat. Cell Biol. 19, 856–863 (2017). sourceNot checked — no full text of the source
• cites [192] Bustillo-Zabalbeitia, I. et al. Specific interaction with cardiolipin triggers functional activation of dynamin-related protein 1. PLoS One 9, e102738 (2014). sourceSupported
  Experimental — accuracy not yet measured
• cites [193] Schlame, M. & Ren, M. The role of cardiolipin in the structural organization of mitochondrial membranes. Biochim. Biophys. Acta 1788, 2080–2083 (2009). sourceCould not verify

  Section 2 discusses cardiolipin’s role in organizing mitochondrial membrane domains and respiratory protein complexes, while Section 5 discusses membrane assembly. Neither addresses regulation of mitochondrial fusion or fission; searches for those processes and mitochondrial dynamics found no relevant passage in our copy. (LLM, conf=0.72)

  Experimental — accuracy not yet measured

Cytochrome c can bind to leucine-rich α2 glycoprotein, a plasma protein elevated during inflammation.

“reports suggest that cytochrome c can bind to leucine-rich α2 glycoprotein, a plasma protein that is elevated during inflammation206,207.”

• cites [206] Shirai, R., Hirano, F., Ohkura, N., Ikeda, K. & Inoue, S. Up-regulation of the expression of leucine-rich α2-glycoprotein in hepatocytes by the mediators of acute-phase response. Biochem. Biophys. Res. Commun. 382, 776–779 (2009). sourceSupported
• cites [207] Druhan, L. J. et al. Leucine rich α-2 glycoprotein: a novel neutrophil granule protein and modulator of myelopoiesis. PLoS One 12, e0170261 (2017). sourceSupported

Programmed necrosis (necroptosis) and pyroptosis induce active release of intact mitochondria into extracellular milieu.

“Moreover, programmed necrosis (known as necroptosis) and pyroptosis induce the active release of intact mitochondria into the extracellular milieu211.”

• cites [211] Davis, M. A. et al. Calpain drives pyroptotic vimentin cleavage, intermediate filament loss, and cell rupture that mediates immunostimulation. Proc. Natl Acad. Sci. USA 116, 5061–5070 (2019). sourcePartly supported

  The section “Rupture of Pyroptotic Cells Releases Macro-DAMPs and Is” (page unavailable) reports mitochondrial DNA and CoxI in supernatants after pyroptotic cells were ruptured by pipetting, and says mitochondrial release from necroptotic cells had been reported. It does not establish that either process actively releases intact mitochondria; its pyroptosis finding depends on cell rupture induced by external shear stress. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

During early apoptosis, cytochrome c changes conformation through interactions with cardiolipin, contributing to cytosolic cytochrome c release and caspase activation.

“Furthermore, during early apoptosis, cytochrome c undergoes conformational changes owing to interactions with cardiolipin, contributing to the subsequent cytosolic release of cytochrome c and caspase activation194.”

• cites [194] Muenzner, J. & Pletneva, E. V. Structural transformations of cytochrome c upon interaction with cardiolipin. Chem. Phys. Lipids 179, 57–63 (2014). sourceSupported

Baseline mitochondrial fMet levels predict development of extra-articular nodules.

“Furthermore, the mitochondrial fMet levels at baseline are predictive of extra-articular nodules development.”

• cites [185] Duvvuri, B. et al. Mitochondrial N-formyl methionine peptides associate with disease activity as well as contribute to neutrophil activation in patients with rheumatoid arthritis. J. Autoimmun. 119, 102630 (2021). sourceSupported

In RA, neutrophils are primed to respond to fMet peptides, shown by high oxidative burst to fMLP ex vivo.

“In this disease, neutrophils are primed to respond to fMet peptides, as shown by the high oxidative burst of neutrophils in response to fMLP, a prototypic bacterial fMet peptide, ex vivo180.”

• cites [180] Eggleton, P., Wang, L., Penhallow, J., Crawford, N. & Brown, K. A. Differences in oxidative response of subpopulations of neutrophils from healthy subjects and patients with rheumatoid arthritis. Ann. Rheum. Dis. 54, 916–923 (1995). sourceSupported

Mitochondrial protein synthesis is initiated by N-formylmethionyl-tRNA, similar to prokaryotes.

“The synthesis of mitochondrial protein is initiated by an N-formylmethionyl-tRNA, similar to that which occurs in prokaryotes176.”

• cites [176] Galper, J. B. Mitochondrial protein synthesis in HeLa cells. J. Cell Biol. 60, 755–763 (1974). sourcePartly supported

  The Abstract (p. 755) says experiments support N-formylmethionyl-tRNA as the initiator of mitochondrial protein synthesis in HeLa cells. The Discussion (pp. 761–762) describes synthesis as appearing to be initiated this way and draws a parallel with prokaryotic ribosomes. The citing sentence states initiation as settled fact, whereas the paper presents it as a supported inference. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Adding mitochondrial fMet measurements improves the prognostic capacity of ACPA positivity to predict erosive disease in RA.

“Incorporating measurements of mitochondrial fMet level can improve the prognostic capacity of ACPA positivity to predict erosive disease in RA.”

• cites [185] Duvvuri, B. et al. Mitochondrial N-formyl methionine peptides associate with disease activity as well as contribute to neutrophil activation in patients with rheumatoid arthritis. J. Autoimmun. 119, 102630 (2021). sourceSupported

Polyreactive aCL antibodies require protein-phospholipid complexes such as those containing β2GPI.

“They contrast with polyreactive aCL antibodies that require the presence of protein–phospholipid complexes such as those containing β2 glycoprotein I (β2GPI, also known as apolipoprotein H)248–250.”

• cites [248] Rauch, J., Tannenbaum, H., Stollar, B. D. & Schwartz, R. S. Monoclonal anti-cardiolipin antibodies bind to DNA. Eur. J. Immunol. 14, 529–534 (1984). sourceNot checked — no full text of the source
• cites [249] Oaks, Z. et al. Mitochondrial dysfunction in the liver and antiphospholipid antibody production precede disease onset and respond to rapamycin in lupus-prone mice. Arthritis Rheumatol. 68, 2728–2739 (2016). sourceCould not verify

  The Materials and Methods (page unavailable) describe separate cardiolipin and β2GPI ELISA coatings, while the Results report aCL and anti-β2GPI antibodies separately. Searches for polyreactivity, protein–phospholipid complexes, and a requirement for β2GPI found no passage in the paper’s discussion or findings establishing the claimed requirement; a cited work’s title in the References is not itself a finding of this paper. (LLM, conf=0.75)

  Experimental — accuracy not yet measured
• cites [250] McNeil, H. P., Simpson, R. J., Chesterman, C. N. & Krilis, S. A. Anti-phospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: β2-glycoprotein I (apolipoprotein H). Proc. Natl Acad. Sci. USA 87, 4120–4124 (1990). sourceNot checked — no full text of the source

Molecular mimicry might explain antigenicity of some mitochondrial proteins and their presentation by MHC II molecules.

“Molecular mimicry might also explain the antigenicity of some mitochondrial proteins and their presentation by MHC II molecules227”

• cites [227] Baum, H. Mitochondrial antigens, molecular mimicry and autoimmune disease. Biochim. Biophys. Acta 1271, 111–121 (1995). sourcePartly supported

  Section 8 proposes that mitochondrial peptides presented with class II HLA could mimic microbial or self-peptides and trigger an autoimmune response. Section 7.1 likewise discusses mimicry involving peptides bound to MHC class II. These passages support a possible explanation for antigenicity, but treat class II presentation as a condition for mimicry, not something mimicry itself explains. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

Stimulated monocytes release extracellular mitochondria capable of stimulating pro-inflammatory cytokine production by endothelial cells.

“Notably, stimulated monocytes also release extracellular mitochondria capable of stimulating the production of pro-inflammatory cytokines by endothelial cells219”

• cites [219] Puhm, F. et al. Mitochondria are a subset of extracellular vesicles released by activated monocytes and induce type I IFN and TNF responses in endothelial cells. Circ. Res. 125, 43–52 (2019). sourceSupported

Positivity for polyreactive aCL antibodies is a classification criterion for APS and SLE.

“Positivity for polyreactive aCL antibodies is a criterion in the classification of two autoimmune conditions: APS and SLE251,252.”

• cites [251] Aringer, M. et al. European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus. Arthritis Rheumatol. 78, 1151–1159 (2019). sourcePartly supported

  The SLE classification-criteria figure lists anti-cardiolipin antibodies as a weighted antiphospholipid-antibody criterion, alongside other requirements for classifying SLE (page not supplied in our copy). It does not specify polyreactive aCL antibodies. This paper sets out SLE criteria, not APS criteria; the sentence also cites another source for APS. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [252] Miyakis, S. et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J. Thromb. Haemost. 4, 295–306 (2006). sourcePartly supported

  The 'Update of the classification criteria' section identifies persistent, medium- or high-titer IgG or IgM aCL positivity as an APS laboratory criterion, with a specified positivity threshold. It does not identify polyreactivity as a criterion or establish aCL positivity as an SLE classification criterion; the SLE portion of the citing sentence may be supported by its other citation, but not by this paper. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Intact mitochondria released during necroptosis can trigger pro-inflammatory responses after engulfment by other immune cells.

“Importantly, the intact mitochondria released during necroptosis can trigger pro-inflammatory responses following engulfment by other immune cells212.”

• cites [212] Maeda, A. & Fadeel, B. Mitochondria released by cells undergoing TNF-α-induced necroptosis act as danger signals. Cell Death Dis. 5, e1312 (2014). sourceSupported

aCL antibody titres in APS and SLE are associated with thrombosis and pregnancy complications.

“aCL antibody titres in these diseases are associated with thrombosis and pregnancy complications253.”

• cites [253] Vreede, A. P., Bockenstedt, P. L. & Knight, J. S. Antiphospholipid syndrome: an update for clinicians and scientists. Curr. Opin. Rheumatol. 29, 458–466 (2017). sourcePartly supported

  The Introduction (page not available) links antiphospholipid antibodies in lupus and APS to thrombotic and obstetric complications, and identifies anticardiolipin positivity in patients with recurrent thrombosis. It does not establish that anticardiolipin antibody titres, specifically, are associated with both thrombosis and pregnancy complications. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

Hydrolysis of mitochondrial membranes by secreted phospholipase A2 group IIA releases pro-inflammatory lipid mediators and mtDNA, which promote neutrophil activation.

“The hydrolysis of mitochondrial membranes by secreted phospholipase A2 group IIA results in the release of pro-inflammatory lipid mediators and mtDNA, which promote neutrophil activation215.”

• cites [215] Boudreau, L. H. et al. Platelets release mitochondria serving as substrate for bactericidal group IIA-secreted phospholipase A2 to promote inflammation. Blood 124, 2173–2183 (2014). sourceSupported

Numerous stimuli, including immune complexes and their combination with TLR ligands, induce platelet activation and subsequent release of extracellular mitochondria.

“In a similar fashion, numerous stimuli, including immune complexes and their combination with TLR ligands, are able to induce platelet activation and subsequent release of extracellular mitochondria214,215.”

• cites [214] Melki, I. et al. Platelets release mitochondrial antigens in systemic lupus erythematosus. Sci. Transl. Med. 13, eaav5928–eaav5928 (2021). sourceNot checked — no full text of the source
• cites [215] Boudreau, L. H. et al. Platelets release mitochondria serving as substrate for bactericidal group IIA-secreted phospholipase A2 to promote inflammation. Blood 124, 2173–2183 (2014). sourcePartly supported

  The Results report that thrombin and other tested platelet stimuli led to the release of extracellular mitochondria. Our copy does not establish that immune complexes, alone or combined with TLR ligands, were among those stimuli; searches for those terms found no such result. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Deletion of β2 microglobulin or CD1d in NZW/NZB F1 murine model of spontaneous SLE reduces circulating aCL antibodies.

“Deletion of β2 microglobulin (an MHC class I molecule) or CD1d (a non-classical MHC protein) in an NZW/NZB F1 murine model of spontaneous SLE results in a reduction of circulating aCL antibodies223,224.”

• cites [223] Singh, R. R., Yang, J. Q., Kim, P. J. & Halder, R. C. Germline deletion of β2 microglobulin or CD1d reduces anti-phospholipid antibody, but increases autoantibodies against non-phospholipid antigens in the NZB/W F1 model of lupus. Arthritis Res. Ther. 15, R47 (2013). sourceSupported
• cites [224] Dieudé, M. et al. Cardiolipin binds to CD1d and stimulates CD1d-restricted γδ T cells in the normal murine repertoire. J. Immunol. 186, 4771–4781 (2011). sourceCould not verify

  The Results section on CD1d-restricted γδ T-cell responses reports experiments in C57BL/6 mice measuring responses to cardiolipin, not circulating anti-cardiolipin antibodies. The Discussion mentions lupus only as a possible setting for these T-cell responses. Searches for β2 microglobulin deletion, NZW/NZB F1 mice, and circulating aCL antibodies found no passage addressing the claimed reduction. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

Later studies confirmed AMA-M5 and antiphospholipid antibodies are distinct autoantibodies.

“however, later studies confirmed that AMA-M5 and antiphospholipid antibodies (aPL; a group comprising lupus anticoagulant, anti-β2GPI antibodies and aCL antibodies) are distinct autoantibodies254,255.”

• cites [254] Labro, M. T., Andrieu, M. C., Weber, M. & Homberg, J. C. A new pattern of non-organ- and non-species-specific anti-organelle antibody detected by immunofluorescence: the mitochondrial antibody number 5. Clin. Exp. Immunol. 31, 357–366 (1978).Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [255] La Rosa, L. et al. Anti-mitochondrial M5 type antibody represents one of the serological markers for anti-phospholipid syndrome distinct from anti-cardiolipin and anti-β2-glycoprotein I antibodies. Clin. Exp. Immunol. 112, 144–151 (1998). sourceSupported

Release of extracellular mitochondria with preserved functions and recapture by other cells might restore mitochondrial functions in recipient cells.

“The release of extracellular mitochondria with preserved functions and their subsequent recapture by other cells might enable the restoration of mitochondrial functions in the recipient cells33,280–282.”

• cites [33] Sun, D., Wei, Y., Zheng, H. X., Jin, L. & Wang, J. Contribution of mitochondrial DNA variation to chronic disease in East Asian populations. Front. Mol. Biosci. 6, 128 (2019). sourceCould not verify

  The Introduction describes mitochondrial function and cybrids made by fusing cells with mitochondrial donors, but not the release and recapture of extracellular mitochondria. Searches for extracellular mitochondria, intercellular transfer, and restoration of recipient-cell function found no passage addressing the claim. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [280] Liu, D. et al. Intercellular mitochondrial transfer as a means of tissue revitalization. Signal. Transduct. Target. Ther. 6, 65 (2021). sourceSupported
• cites [281] Sinha, P., Islam, M. N., Bhattacharya, S. & Bhattacharya, J. Intercellular mitochondrial transfer: bioenergetic crosstalk between cells. Curr. Opin. Genet. Dev. 38, 97–101 (2016). sourceSupported
• cites [282] Torralba, D., Baixauli, F. & Sanchez-Madrid, F. Mitochondria know no boundaries: mechanisms and functions of intercellular mitochondrial transfer. Front. Cell Dev. Biol. 4, 107 (2016). sourceSupported

The balance between glycolysis and oxidative phosphorylation not only defines ATP yield but might also affect oxidation levels and consumption of metabolites such as glucose and fatty acids.

“The balance between glycolysis and oxidative phosphorylation in providing energy for the cell not only defines the yield of ATP production but might also affect the levels of oxidation (for example, through the production of mtROS) and the consumption of metabolites (such as glucose and fatty acids)273,274.”

• cites [273] Tokarska, K., Majsterek, I., Cuchra, M. & Wozniacka, A. Immunometabolic disorders in the pathogenesis of systemic lupus erythematosus. Postepy Dermatol. Alergol. 36, 513–518 (2019). sourcePartly supported

  The Respiratory chain section (page unavailable) says oxidative phosphorylation retains energy in ATP, and the Reactive oxygen species section (page unavailable) says cellular respiration produces mitochondrial ROS. The copy does not say that the balance between glycolysis and oxidative phosphorylation determines ATP yield or affects oxidation levels and consumption of glucose or fatty acids. (LLM, conf=0.83)

  Experimental — accuracy not yet measured
• cites [274] Weyand, C. M. & Goronzy, J. J. Immunometabolism in the development of rheumatoid arthritis. Immunol. Rev. 294, 177–187 (2020). sourceSupported

Detection of mitochondrial motives by innate and adaptive immunity might elicit potent pro-inflammatory responses.

“Given the bacterial features of mitochondria, the detection of mitochondrial motives by cells of the innate and adaptive immunity might elicit potent pro-inflammatory responses147,276,277.”

• cites [147] West, A. P. et al. Mitochondrial DNA stress primes the antiviral innate immune response. Nature 520, 553–557 (2015). sourcePartly supported

  The paper’s Abstract reports that cytosolic mitochondrial DNA engages an innate immune sensor and potentiates type I interferon responses. It does not establish detection by adaptive immune cells or a broad, potent pro-inflammatory response; the demonstrated response is specifically antiviral innate signaling. The indexed passages provide no page number. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [276] Pisetsky, D. S., Gauley, J. & Ullal, A. J. Microparticles as a source of extracellular DNA. Immunol. Res. 49, 227–234 (2011). sourceCould not verify

  The Introduction discusses immune responses to bacterial CpG motifs and to DNA-containing immune complexes, but it does not address mitochondrial motifs or their detection by innate and adaptive immune cells. Searches for mitochondrial DNA, mitochondria, and mitochondrial motifs found no passage supporting the attributed claim. The available passages have no page numbers. (LLM, conf=0.75)

  Experimental — accuracy not yet measured
• cites [277] Nunnari, J. & Suomalainen, A. Mitochondria: in sickness and in health. Cell 148, 1145–1159 (2012). sourcePartly supported

  The Introduction describes mitochondria’s bacterial ancestry, and “Mitochondrial Defects Cause Diverse and Complex Human Diseases” says that the innate immune system recognizes and targets mouse cells with allogenic mtDNA. Our copy does not say that adaptive immunity detects mitochondrial motifs or that such detection elicits potent pro-inflammatory responses. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

Transfer of mitochondria between cells might occur via cellular fusion or tunnelling nanotubes.

“In addition to the release of mitochondria (as free organelle or encapsulated in extracellular vesicles) and their capture by recipient cells, the transfer of mitochondria between cells might occur via cellular fusion or tunnelling nanotubes283–285.”

• cites [283] Rustom, A., Saffrich, R., Markovic, I., Walther, P. & Gerdes, H. H. Nanotubular highways for intercellular organelle transport. Science 303, 1007–1010 (2004). sourceNot checked — no full text of the source
• cites [284] Miliotis, S., Nicolalde, B., Ortega, M., Yepez, J. & Caicedo, A. Forms of extracellular mitochondria and their impact in health. Mitochondrion 48, 16–30 (2019). sourcePartly supported

  Section 5 says mitochondrial transfer from a donor cell can occur through nanotubes, supporting that route. It does not describe transfer through cellular fusion: its discussion of fusion concerns exogenous mitochondria joining the recipient cell’s mitochondrial network after uptake, not the fusion of two cells. No page number is available in our copy. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [285] Golan, K. et al. Bone marrow regeneration requires mitochondrial transfer from donor Cx43-expressing hematopoietic progenitors to stroma. Blood 136, 2607–2619 (2020). sourcePartly supported

  The Introduction says mitochondrial transfer can occur via tunneling nanotubes, and the Results describe cell-contact-dependent transfer between hematopoietic progenitors and bone marrow stromal cells. Neither passage identifies cellular fusion as a transfer mechanism, so the source supports only the nanotube part of the claim. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Research into active release of mitochondria into extracellular milieu led to discovery of transmitophagy, a cell-to-cell communication type contributing to inflammation and tissue rejuvenation.

“Research into the active release of mitochondria into the extracellular milieu212,214,278 has led to the discovery of a new type of cell-to-cell communication, termed ‘transmitophagy’, that contributes to both inflammation and tissue rejuvenation.”

• cites [212] Maeda, A. & Fadeel, B. Mitochondria released by cells undergoing TNF-α-induced necroptosis act as danger signals. Cell Death Dis. 5, e1312 (2014). sourceSupported
• cites [214] Melki, I. et al. Platelets release mitochondrial antigens in systemic lupus erythematosus. Sci. Transl. Med. 13, eaav5928–eaav5928 (2021). sourceNot checked — no full text of the source
• cites [278] Marcoux, G. et al. Microparticle and mitochondrial release during extended storage of different types of platelet concentrates. Platelets 28, 272–280 (2017). sourceNot checked — no full text of the source

Antibodies to mitochondrial nucleic acids (mtDNA and mtRNA) are present in SLE or APS patients.

“Antibodies to mitochondrial nucleic acids (mtDNA and mtRNA) are also present in patients with SLE or APS230,231,261,262.”

• cites [230] Becker, Y. et al. Anti-mitochondrial autoantibodies in systemic lupus erythematosus and their association with disease manifestations. Sci. Rep. 9, 4530 (2019). sourcePartly supported

  The Results (Figure 4; page not provided) report elevated anti-mtDNA antibodies in SLE patients, but not in the APS patients tested. The paper does not report antibodies to mtRNA, so it supports only the SLE/mtDNA part of the claim. (LLM, conf=0.90)

  Experimental — accuracy not yet measured
• cites [231] Becker, Y. et al. Autoantibodies in systemic lupus erythematosus target mitochondrial RNA. Front. Immunol. 10, 1026 (2019). sourceSupported
• cites [261] Becker, Y. L., Julien, A. S., Godbout, A., Boilard, E. & Fortin, P. R. Pilot study of anti-mitochondrial antibodies in antiphospholipid syndrome. Lupus 29, 1623–1629 (2020). sourceNot checked — no full text of the source
• cites [262] Pisetsky, D. S. et al. The binding of SLE autoantibodies to mitochondria. Clin. Immunol. 212, 108349 (2020). sourcePartly supported

  The Discussion (page unavailable) reports anti-DNA and anti-whole-mitochondrion reactivity in SLE patients, but says the DNA target could be mitochondrial, nuclear, or a cross-reactive antigen. The paper does not establish antibodies specifically to mtDNA or mtRNA, and it does not report findings in APS patients. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Mass spectrometry identified 431 mitochondrial proteins co-precipitating with autoantibodies from SLE patients.

“Using mass spectrometry, researchers have attempted to identify the mitochondrial targets of these autoantibodies: in this study, 431 mitochondrial proteins (and hence potential targets) co-precipitated with autoantibodies from patients with SLE266.”

• cites [266] Becker, Y. L. et al. Identification of mitofusin 1 and complement component 1q subcomponent-binding protein as mitochondrial targets in systemic lupus erythematosus. Arthritis Rheumatol. https://doi.org/10.1002/art.42082 (2022). sourceSupported

Autoantibodies against mitofusin 1 and C1qBP were elevated in a cohort of SLE patients.

“Among these targets, autoantibodies against mitofusin 1 and C1qBP were elevated in a cohort of patients with SLE266.”

• cites [266] Becker, Y. L. et al. Identification of mitofusin 1 and complement component 1q subcomponent-binding protein as mitochondrial targets in systemic lupus erythematosus. Arthritis Rheumatol. https://doi.org/10.1002/art.42082 (2022). sourceSupported
  Experimental — accuracy not yet measured

In vitro transfer of healthy mitochondria to CD4+ T cells from RA patients can restore aspartate metabolism and decrease TNF production compared with untreated controls.

“Moreover, the in vitro transfer of healthy mitochondria to CD4+ T cells from patients with RA can restore aspartate metabolism and decrease the production of TNF, compared with untreated controls286–288.”

• cites [286] Wu, T. H. et al. Mitochondrial transfer by photothermal nanoblade restores metabolite profile in mammalian cells. Cell Metab. 23, 921–929 (2016). sourcePartly supported

  The Results sections “Mitochondrial Transfer” and “Metabolite Profiling” (page not provided) report mitochondrial transfer into mtDNA-depleted ρ0 cells and restoration of their overall metabolite profile. They do not report experiments in CD4+ T cells from patients with rheumatoid arthritis, restoration of aspartate metabolism, or decreased TNF production; searches for those terms found no supporting passage. (LLM, conf=0.83)

  Experimental — accuracy not yet measured
• cites [287] Rogers, R. S. & Bhattacharya, J. When cells become organelle donors. Physiology 28, 414–422 (2013). sourceNot checked — no full text of the source
• cites [288] Wu, B. et al. Mitochondrial aspartate regulates TNF biogenesis and autoimmune tissue inflammation. Nat. Immunol. 22, 1551–1562 (2021). sourceSupported

Cells with mitochondrial defects might release damaged mitochondria to be picked up by other cells, facilitating degradation by recipient cells.

“Cells with mitochondrial defects might release the damaged mitochondria to be picked up by other cells, thereby facilitating their degradation by recipient cells279.”

• cites [279] Davis, C. H. et al. Transcellular degradation of axonal mitochondria. Proc. Natl Acad. Sci. USA 111, 9633–9638 (2014). sourcePartly supported

  The Significance section and Discussion report that retinal ganglion cell axons shed mitochondria that adjoining astrocytes take up and degrade. The study describes otherwise healthy axons in wild-type mice; it does not establish that the releasing cells had mitochondrial defects or that the shed mitochondria were damaged. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Investigations of mitochondrial DNA SNPs and haplogroups in SLE and rheumatoid arthritis suggest that mitochondrial DNA alterations may be useful as early markers of diagnosis, disease activity and progression.

“investigations of mtDNA SNPs and haplogroups in SLE and RA suggest the potential utility of mtDNA alterations as early markers of diagnosis, disease activity and progression”

In ankylosing spondylitis, calcium hydroxyapatite deposits found near mitochondria suggest that mitochondrial calcium regulation may be involved in the disease.

“in ankylosing spondylitis, deposits of calcium hydroxyapatite are often found in close proximity to mitochondria, suggesting that calcium regulation by the organelle might be involved in the disease50”

• cites [50] Sampson, H. W., Davis, R. W. & Dufner, D. C. Spondyloarthropathy in progressive ankylosis mice: ultrastructural features of the intervertebral disk. Acta Anat. 141, 36–41 (1991). sourceNot checked — no full text of the source

Mitochondrial DNA SNP analysis has revealed enrichment of variants in the D-loop region and MT-ATP6 in rheumatoid arthritis.

“MtDNA SNP data analysis has revealed enrichment of variants in the D-loop region and MT-ATP6 in RA”

• cites [45] Jaiswal, K. S. et al. Differential mitochondrial genome in patients with rheumatoid arthritis. Autoimmunity 54, 1–12 (2021). sourceNot checked — no full text of the source
• cites [46] Du, J. et al. Germline and somatic mtDNA mutation spectrum of rheumatoid arthritis patients in the Taizhou area, China. Rheumatology 59, 2982–2991 (2020). sourceNot checked — no full text of the source

Advancements since the 2010s indicate that mitochondria have a role in rheumatic diseases.

“Advancements made since the 2010s, which are reviewed herein, point to a role for the mitochondria in rheumatic diseases”

Ex vivo studies indicate that mitochondrial reactive oxygen species can inhibit neutrophil apoptosis through the NF-κB pathway.

“ex vivo studies indicate that mtROS can inhibit neutrophil apoptosis through the NF-ĸB pathway58”

• cites [58] Vorobjeva, N. et al. Mitochondrial reactive oxygen species are involved in chemoattractant-induced oxidative burst and degranulation of human neutrophils in vitro. Eur. J. Cell Biol. 96, 254–265 (2017). sourceNot checked — no full text of the source

MT-ATP6 variant enrichment in rheumatoid arthritis is mainly driven by m.8830 C>A, m.8833 G>C and m.8843 T>A SNPs predicted to be pathogenic.

“MT-ATP6 variant enrichment is mainly driven by m.8830 C > A, m.8833 G > C and m.8843 T > A SNPs that are predicted to be pathogenic46”

• cites [46] Du, J. et al. Germline and somatic mtDNA mutation spectrum of rheumatoid arthritis patients in the Taizhou area, China. Rheumatology 59, 2982–2991 (2020). sourceNot checked — no full text of the source

After intact mitochondria or mitochondrial components are released into the cytosol or extracellular space, their bacteria-like molecular motifs can trigger innate pro-inflammatory responses.

“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”

Mitochondria can sense and store calcium released from the endoplasmic reticulum, thereby regulating its availability.

“mitochondria can also sense and store calcium released from the endoplasmic reticulum, thus regulating its availability48,49”

• cites [48] Kirichok, Y., Krapivinsky, G. & Clapham, D. E. The mitochondrial calcium uniporter is a highly selective ion channel. Nature 427, 360–364 (2004). sourceNot checked — no full text of the source
• cites [49] Rizzuto, R. et al. Close contacts with the endoplasmic reticulum as determinants of mitochondrial Ca2+ responses. Science 280, 1763–1766 (1998). sourceNot checked — no full text of the source

The D-loop hypervariable region III variant at position 513 is enriched in patients with rheumatoid arthritis compared with healthy individuals.

“the variant at the 513 position of D-loop hypervariable region III is enriched in patients with RA compared with healthy individuals45”

• cites [45] Jaiswal, K. S. et al. Differential mitochondrial genome in patients with rheumatoid arthritis. Autoimmunity 54, 1–12 (2021). sourceNot checked — no full text of the source

Mitochondrial dysregulation may contribute to the pathophysiology of several autoimmune diseases.

“dysregulation of mitochondria possibly contributes to the pathophysiology of several autoimmune diseases”

In vivo data indicate that increased oxidative stress in SLE T cells leads to exhaustion of their antioxidant capacity.

“Data from in vivo studies indicate that this increased oxidative stress leads to exhaustion of the antioxidant capacity of the T cells34”

• cites [34] Gergely, P. Jr et al. Mitochondrial hyperpolarization and ATP depletion in patients with systemic lupus erythematosus. Arthritis Rheum. 46, 175–190 (2002). sourceNot checked — no full text of the source

In NZB/W F1 mice fed a cholesterol-rich diet, taurine supplementation inhibits mitochondrial-dependent apoptosis.

“in NZB/W F1 mice (a spontaneous model of SLE) fed a cholesterol-rich diet, supplementation with taurine inhibited mitochondrial-dependent apoptosis89”

• cites [89] Hsu, T. C. et al. Treatment with taurine attenuates hepatic apoptosis in NZB/W F1 mice fed with a high-cholesterol diet. J. Agric. Food Chem. 56, 9685–9691 (2008). sourceNot checked — no full text of the source

C1q is thought to have protective functions in SLE pathogenesis through the waste disposal hypothesis because of its role in clearing apoptotic debris.

“The classical pathway of complement, and particularly C1q, is thought to have protective functions in SLE pathogenesis via the ‘waste disposal hypothesis’, given the role of C1q in clearing apoptotic debris77,78”

• cites [77] Manderson, A. P., Botto, M. & Walport, M. J. The role of complement in the development of systemic lupus erythematosus. Annu. Rev. Immunol. 22, 431–456 (2004). sourceNot checked — no full text of the source
• cites [78] Walport, M. J. Lupus, DNase and defective disposal of cellular debris. Nat. Genet. 25, 135–136 (2000). sourceNot checked — no full text of the source

The potential bacterial origin of mitochondria may provide features recognized by innate immunity after release of intact organelles or fragmented components extracellularly.

“The potential bacterial origin of mitochondria might provide features that are recognized by the innate immune system following the release of intact organelles or fragmented mitochondrial components into the extracellular milieu.”

Mitochondria exchange molecules with other organelles by generating mitochondria-derived vesicles in cytosol, controlled by PINK1.

“Mitochondria can exchange molecules with other organelles within the cell by generating mitochondria-derived vesicles in the cytosol, a process under the control of PINK1 (REF.151).”

• cites [151] McLelland, G. L., Soubannier, V., Chen, C. X., McBride, H. M. & Fon, E. A. Parkin and PINK1 function in a vesicular trafficking pathway regulating mitochondrial quality control. EMBO J. 33, 282–295 (2014). sourceNot checked — no full text of the source

Dysregulation of mitochondrial-dependent programmed cell death might contribute to inflammation in autoimmune and rheumatic conditions.

“Dysregulation of mitochondrial-dependent programmed cell death might thus contribute to inflammation in autoimmune and rheumatic conditions”

Different mitochondrial stressors engage distinct nucleic acid sensors depending on availability of mitochondrial-derived nuclear components.

“suggesting that different mitochondrial stressors engage unique nucleic acid sensors driven by the availability of the mitochondrial-derived nuclear component.”

Dysregulated mitochondrial dynamics has a role in rheumatic diseases.

“Overall, these studies suggest that dysregulated mitochondrial dynamics has a role in rheumatic diseases”

Cardiolipin might contribute to rheumatic diseases independently of its antigenicity.

“Thus, with its roles in mitochondrial integrity and functions, cardiolipin might also contribute to rheumatic diseases independently of its antigenicity.”

Intra-articular injection of cytochrome c induces NF-κB-mediated arthritis in mice.

“Intra-articular injection of cytochrome c induces NF-ĸB-mediated arthritis in mice208.”

• cites [208] Pullerits, R., Bokarewa, M., Jonsson, I. M., Verdrengh, M. & Tarkowski, A. Extracellular cytochrome c, a mitochondrial apoptosis-related protein, induces arthritis. Rheumatology 44, 32–39 (2005). sourceNot checked — no full text of the source

Extracellular ATP can activate CD8+ T cells from RA patients after ex vivo co-incubation.

“Furthermore, extracellular ATP can activate CD8+ T cells from patients with RA following ex vivo co-incubation201.”

• cites [201] Tripathy, A., Padhan, P., Swain, N., Raghav, S. K. & Gupta, B. Increased extracellular ATP in plasma of rheumatoid arthritis patients activates CD8+ T cells. Arch. Med. Res. 52, 423–433 (2021). sourceNot checked — no full text of the source

ATP concentrations are highly compartmentalized, with about a thousand-fold difference between nanomolar extracellular and micromolar cytosolic concentrations.

“ATP concentrations are highly compartmentalized, with approximately a thousand-fold difference between the nanomolar concentrations found in the extracellular space and the micromolar concentrations found in the cytosol.”

The circulating autoantibody repertoire in SLE patients includes IgG antibodies targeting cytochrome c.

“Interestingly, the circulating autoantibody repertoire in patients with SLE includes IgG antibodies that target cytochrome c209.”

• cites [209] Mamula, M. J., Jemmerson, R. & Hardin, J. A. The specificity of human anti-cytochrome c autoantibodies that arise in autoimmune disease. J. Immunol. 144, 1835–1840 (1990). sourceNot checked — no full text of the source

Circulating ATP levels are increased in RA patients compared with healthy individuals.

“For example, the levels of circulating ATP are increased in patients with RA compared with healthy individuals.”

Circulating cytochrome c levels are present in inflammatory conditions such as arthritis, psoriasis, and SLE.

“Consistent with the release of mitochondrial components during cell death (FIG. 5), circulating levels of cytochrome c are present in inflammatory conditions such as arthritis, psoriasis or SLE205.”

• cites [205] Adachi, N. et al. Serum cytochrome c level as a prognostic indicator in patients with systemic inflammatory response syndrome. Clin. Chim. Acta 342, 127–136 (2004). sourceNot checked — no full text of the source

Fibroblasts contribute to skin fibrosis in systemic sclerosis through P2Y-mediated inflammation.

“Finally, fibroblasts contribute to skin fibrosis in systemic sclerosis through P2Y-mediated inflammation204.”

• cites [204] Perera, L. M. B. et al. The regulation of skin fibrosis in systemic sclerosis by extracellular ATP via P2Y2 purinergic receptor. J. Invest. Dermatol. 139, 890–899 (2019). sourceNot checked — no full text of the source

Non-covalent interactions between cardiolipin and proteins are necessary for mitochondrial functions such as energy supply.

“Non-covalent interactions between cardiolipin and various proteins are necessary for various mitochondrial functions such as energy supply.”

AMA-M5 are complement-fixing autoantibodies targeting unknown mitochondrial antigens.

“AMA-M5 are complement-fixing autoantibodies that target unknown mitochondrial antigens.”

Naked mitochondria are endogenous substrates for secreted phospholipase A2 group IIA, an enzyme potent at hydrolysing Gram-positive bacteria.

“Naked mitochondria are endogenous substrates for secreted phospholipase A2 group IIA, a secreted enzyme that is highly potent at hydrolysing Gram-positive bacteria.”

AMA profiling in PBC patients has improved diagnosis and prognosis.

“AMA profiling of patients with PBC has enabled researchers to improve both diagnosis and prognosis of the disease229,237.”

• cites [229] Berg, P. A. & Klein, R. Mitochondrial antigens and autoantibodies: from anti-M1 to anti-M9. Klin. Wochenschr. 64, 897–909 (1986). sourceNot checked — no full text of the source
• cites [237] Berg, P. A. & Klein, R. Mitochondrial antigen/antibody systems in primary biliary cirrhosis: revisited. Liver 15, 281–292 (1995). sourceNot checked — no full text of the source

Most mtDNA in plasma of SLE patients originates from naked mitochondria.

“Intriguingly, most of the mtDNA present in the plasma of patients with SLE originates from naked mitochondria214.”

• cites [214] Melki, I. et al. Platelets release mitochondrial antigens in systemic lupus erythematosus. Sci. Transl. Med. 13, eaav5928–eaav5928 (2021). sourceNot checked — no full text of the source

Given the pro-inflammatory milieu of SLE and RA, necroptosis-induced active release of pro-inflammatory mitochondria might also occur in these diseases.

“Given the pro-inflammatory milieu of SLE and RA, this mechanism of necroptosis-induced active release of pro-inflammatory mitochondria might also occur under these disease conditions.”

H2-M3, an MHC class Ib molecule, has affinity for short N-formylated peptides such as those encoded by the mitochondrial genome.

“Furthermore, H2-M3, a MHC class Ib molecule, has an affinity for short N-formylated peptides such as those encoded by the mitochondrial genome222.”

• cites [222] Dabhi, V. M. & Lindahl, K. F. Short peptides sensitize target cells to CTL specific for the MHC class Ib molecule, H2-M3. Eur. J. Immunol. 28, 3773–3782 (1998). sourceNot checked — no full text of the source

A humoral response to mitochondrial antigens, comprising anti-mitochondrial antibodies targeting various organelle epitopes, occurs.

“however, a humoral response to mitochondrial antigens, comprising anti-mitochondrial antibodies targeting various organelle epitopes, also occurs.”

AMA-M5 and aCL antibodies have similar associations with disease manifestations such as thrombosis and fetal loss.

“AMA-M5 and aCL antibodies have similar associations with disease manifestations (such as associations with thrombosis and fetal loss)256.”

• cites [256] Desamparados, O.-M., Sanchez-Ramón, S., Rodriguez-Mahou, M., Alvarez, S. & Fernández-Cruz, E. Isolated type 5 antimitochondrial autoantibodies are associated with a history of thrombocytopenia and fetal loss. Fertil. Steril. 87, 917–976 (2007).Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Naturally occurring mitochondrial antibodies (IgG, IgM, IgA) are produced in absence of detectable disease and without known immunization with mitochondrial epitopes.

“These natural antibodies (including IgG, IgM and IgA antibodies) are produced in the absence of any detectable disease and without any known immunization with mitochondrial epitopes267,268.”

• cites [267] Berg, P. A. & Klein, R. Antimitochondrial antibodies in primary biliary cirrhosis and other disorders: definition and clinical relevance. Dig. Dis. 10, 85–101 (1992). sourceNot checked — no full text of the source
• cites [268] Czompoly, T. et al. Detailed analyses of antibodies recognizing mitochondrial antigens suggest similar or identical mechanism for production of natural antibodies and natural autoantibodies. Autoimmun. Rev. 7, 463–467 (2008). sourceNot checked — no full text of the source

Anti-mtRNA and anti-mtDNA antibodies can cross-react with other autoantigens, similar to anti-Th/To autoantibodies in systemic sclerosis cross-reacting with mitochondrial ribonucleoproteins.

“These antibodies can also cross-react with other autoantigens, similar to how anti-Th/To autoantibodies in systemic sclerosis can cross-react with ribonucleoproteins of the mitochondrion263.”

• cites [263] Mahler, M., Fritzler, M. J. & Satoh, M. Autoantibodies to the mitochondrial RNA processing (MRP) complex also known as Th/To autoantigen. Autoimmun. Rev. 14, 254–257 (2015). sourceNot checked — no full text of the source