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Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency
Open accessAbstract
Opa1 participates in inner mitochondrial membrane fusion and cristae morphogenesis. Here, we show that muscle-specific Opa1 ablation causes reduced muscle fiber size, dysfunctional mitochondria, enhanced Fgf21, and muscle inflammation characterized by NF-κB activation, and enhanced expression of pro-inflammatory genes. Chronic sodium salicylate treatment ameliorated muscle alterations and reduced the muscle expression of Fgf21. Muscle inflammation was an early event during the progression of the disease and occurred before macrophage infiltration, indicating that it is a primary response to Opa1 deficiency. Moreover, Opa1 repression in muscle cells also resulted in NF-κB activation and inflammation in the absence of necrosis and/or apoptosis, thereby revealing that the activation is a cell-autonomous process and independent of cell death. The effects of Opa1 deficiency on the expression NF-κB target genes and inflammation were absent upon mitochondrial DNA depletion. Under Opa1 deficiency, blockage or repression of TLR9 prevented NF-κB activation and inflammation. Taken together, our results reveal that Opa1 deficiency in muscle causes initial mitochondrial alterations that lead to TLR9 activation, and inflammation, which contributes to enhanced Fgf21 expression and to growth impairment.
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TL;DR
Muscle-specific loss of Opa1 in mice produces mitochondrial dysfunction, mtDNA stress, and a primary inflammatory response that precedes macrophage infiltration and contributes to growth impairment. The inflammatory NF-κB program depends on mtDNA and TLR9, and anti-inflammatory salicylate treatment partially rescues muscle and growth phenotypes.
Key findings
- Opa1 ablation in skeletal muscle shortened lifespan, reduced body growth, muscle weight, grip strength, and myofiber cross-sectional area, and altered the GH/IGF1 axis; muscle Fgf21 was strongly induced and circulating Fgf21 was about fourfold higher.
- Inflammation appeared early: IL-1β labeling was already elevated at 3 weeks, while CD68-positive macrophages were not detected until 13 weeks; NF-κB target genes and plasma IL-1β/IL-6 were increased.
- Opa1 deficiency caused mitochondrial fragmentation, reduced respiration, increased glycolysis, and mtDNA stress, including roughly 50% lower mtDNA copy number, about half the TFAM protein, fewer nucleoids, and larger nucleoids.
- The inflammatory response required mtDNA and TLR9: ethidium bromide treatment depleted mtDNA by more than 95% and abolished NF-κB target gene induction, while TLR9 antagonism or TLR9 knockdown reduced NF-κB target genes and IL-6 release; mtDNA co-localized with TLR9 in over 50% of signal.
Methods
- Mouse models included muscle-specific Opa1 knockout via Opa1-loxP/loxP crossed with myogenin-Cre, tamoxifen-inducible adult muscle Opa1 knockout, cardiotoxin injury with adenoviral Opa1 miRNA, and Opa1/Fgf21 double knockout; treatments included sodium salicylate and chloroquine.
- Cell studies used C2C12 myoblasts with Opa1 knockdown, ethidium bromide-mediated mtDNA depletion, cGAS or TLR9 knockdown, and ODN2088 TLR9 antagonist treatment.
- Analyses included histology, immunofluorescence, electron microscopy, mitochondrial respiration, Seahorse extracellular flux, ATP measurement, mtDNA quantification, Western blotting, plasma cytokine/hormone assays, gene expression, and t-tests or ANOVA with post hoc tests at P < 0.05.
Limitations
- The paper states that mitophagy measurements are difficult in skeletal muscle and that further work is needed to document Opa1’s impact on muscle mitophagy.
- The paper states that the precise mechanism by which mtDNA interacts with TLR9 remains unclear, that robust demonstration is lacking, and that mitochondria-derived vesicle involvement cannot be excluded.
- The paper notes that localization of mtDNA or mitochondria to late endosomes could not be concluded because triple staining was lacking; more broadly, the evidence is largely from mouse and C2C12 models, with human inflammatory myopathy relevance proposed rather than directly tested.
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“and also CK activity was normalized (Fig 4D), consistent with reduced muscle necrosis.”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Salicylate treatment reduces inflammation and improves growth in Opa1 KO mice
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In the paper
“dysfunctional mitochondria”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Abstract
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In the paper
“Under Opa1 deficiency, blockage or repression of TLR9 prevented NF-jB activation and inflammation.”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Abstract
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In the paper
“The effects of Opa1 deficiency on the expression NF-jB target genes and inflammation were absent upon mitochondrial DNA depletion.”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Abstract
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In the paper
“EtBr-treated cells showed a 95% reduction of mtDNA in Opa1-deficient cells (Fig 6A and Appendix Fig S3A).”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Opa1 deficiency-driven inflammation requires mtDNA and is independent of cGAS
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: Ethidium bromide treatment depletes mtDNA without affecting other cellular processes relevant to NF-kB target gene expression.
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In the paper
“whereas Opa1-deficient muscles showed sustained high expression of dMHC (Figs 1C and EV1D)”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Skeletal muscle-specific Opa1 ablation causes reduced body growth and premature death
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In the paper
“Opa1 ablation in this specific tissue induced a dramatic reduction in life span (Fig 1E)”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Skeletal muscle-specific Opa1 ablation causes reduced body growth and premature death
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“and unaltered ATP levels (Fig 5J).”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Opa1 depletion causes mitochondrial dysfunction and mitochondrial DNA stress
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In the paper
“histological analyses of KO mice indicated a marked decrease in fiber size and cross-sectional area in quadriceps and diaphragm (Figs 1I and EV1J, K and L).”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Skeletal muscle-specific Opa1 ablation causes reduced body growth and premature death
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In the paper
“No evidence of apoptosis was detected in muscles of control or KO mice (Fig EV2A).”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Opa1 ablation causes inflammatory myopathy
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“Opa1deficient muscles showed increased levels of various mitochondrial proteins, but neither of OXPHOS subunits nor of Pgc-1a expression (Fig 5B and C and Appendix Fig S2A).”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Opa1 depletion causes mitochondrial dysfunction and mitochondrial DNA stress
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In the paper
“Opa1 deficiency also caused decreased mitochondrial respiration, which was characterized by enhanced respiratory leak and reduced maximal respiratory capacity (Fig 5H)”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Opa1 depletion causes mitochondrial dysfunction and mitochondrial DNA stress
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“Nucleoid composition analysis by confocal microscopy revealed a reduction in the number of nucleoids per cell (Fig 5M) and enhanced nucleoid size (Fig 5N).”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Opa1 depletion causes mitochondrial dysfunction and mitochondrial DNA stress
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“Chronic sodium salicylate treatment ameliorated muscle alterations and reduced the muscle expression of Fgf21.”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Abstract
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In the paper
“Opa1 KO mice showed enhanced expression of hepatic genes relevant in gluconeogenesis, lipid metabolism, or mitochondrial respiration, and DKO mice showed a normalized expression (Fig 2H).”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Skeletal muscle-specific Opa1 ablation causes reduced body growth and premature death
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“Histological inspection of Opa1-deficient muscle sections revealed a substantial number of necrotic myofibers, as well as regenerating fibers (centrally located nuclei; Fig 3A).”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Opa1 ablation causes inflammatory myopathy
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“Salicylate treatment markedly reduced plasma GH (Fig 4E), increased the hepatic expression of Ghr, Igf1, and Fos (Figs 4F and EV3F and G), and reduced SOCS3 expression (Fig 4G).”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Salicylate treatment reduces inflammation and improves growth in Opa1 KO mice
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“Anti-inflammatory efficiency was documented by low expression of NF-jB target genes and by low circulating levels of IL-6 and IL-1b (Fig EV3A-C).”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Salicylate treatment reduces inflammation and improves growth in Opa1 KO mice
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“and decreased expression of its target genes Igf1 and Fos (Fig 2B).”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Skeletal muscle-specific Opa1 ablation causes reduced body growth and premature death
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“There were no changes in mitochondrial mass, as the expression of mitochondrial proteins PORIN, TIM44, SDHA, or TOM20 was not reduced in Opa1-deficient cells (Fig 5G).”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Opa1 depletion causes mitochondrial dysfunction and mitochondrial DNA stress
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“Opa1 KD myoblasts (Fig EV3C) showed a marked increase of NF-jB promoter activity (Fig 3F) and the expression of NF-jB target genes (Fig 3G).”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Opa1 ablation causes inflammatory myopathy
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“muscle inflammation characterized by NF-jB activation, and enhanced expression of pro-inflammatory genes.”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Abstract
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“Also, it revealed reduced expression of growth hormone receptor (Ghr) and increased expression of the STAT5 inhibitor Socs3 (Fig 2B).”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Skeletal muscle-specific Opa1 ablation causes reduced body growth and premature death
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“Muscle inflammation was an early event during the progression of the disease and occurred before macrophage infiltration”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Abstract
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“Highly positive labeling for IL-1b was already detected at 3 weeks in Opa1-deficient muscles and was maintained with age (Fig 3D and Appendix Fig S1A).”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Opa1 ablation causes inflammatory myopathy
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In the paper
“Opa1 deficiency did not cause necrosis (Fig EV2D) or apoptosis (Fig EV2E and F).”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Opa1 ablation causes inflammatory myopathy
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“Analysis of mitochondrial morphology showed a markedly altered organization of the mitochondrial network and an enhanced mitochondrial density (Fig 5A).”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Opa1 depletion causes mitochondrial dysfunction and mitochondrial DNA stress
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In the paper
“We also found hepatic alterations in Opa1 KO mice such as enhanced Socs3 expression, reduced STAT5 phosphorylation, reduced gene expression of growth hormone receptor, and lower expression of growth hormone target genes.”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Discussion
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“A rapid recruitment of LC3-II to mitochondrial enriched fractions was detected upon incubation with CCCP for 30 min in both control and Opa1-deficient cells, suggesting a normal mitophagy induction in Opa1-deficient cells (Fig 7A and Appendix Fig S4C).”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Opa1 deficiency disrupts mitophagy completion in muscle cells
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- Rests on an assumption: CCCP induces mitochondrial depolarization and mitophagy in these cells.
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In the paper
“we did not detect induction of interferon-stimulated genes neither Ifnb in Opa1deficient cells (Fig 6E)”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Opa1 deficiency-driven inflammation requires mtDNA and is independent of cGAS
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“This is characterized by mitochondrial fragmentation, reduced mitochondrial respiration, normal or enhanced expression of mitochondrial proteins, and unaltered expression of the mitochondrial biogenesis factor PGC1a.”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Discussion
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“Time-course studies revealed significantly increased levels of p62 and presence of ragged red fibers in the muscles of 3-week-old mice, which further accumulated with age (Fig 7H, Appendix Fig S4H and I).”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Opa1 deficiency disrupts mitophagy completion in muscle cells
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- Rests on an assumption: p62 accumulation reflects impaired autophagic flux in muscle.
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“Analysis of double knockout mice proved that, although the hepatic expression of metabolic genes was restored, the growth defects due to Opa1 deficiency were independent of FGF21.”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Discussion
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In the paper
“The characterization of the Opa1 KO mice growth defects revealed low levels of circulating Igf1, high plasma growth hormone, and high Fgf21 expression in muscle as well as in circulation.”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Discussion
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“Furthermore, chronic treatment with salicylate resulted in substantial amelioration of muscle mass, body weight, muscle necrosis, and hepatic growth hormone resistance.”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Discussion
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“Salicylate treatment reduces inflammation and improves growth in Opa1 KO mice.”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Statistics
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“Here, we document that Opa1 deficiency was characterized by reduced mtDNA copy number, parallel to diminished TFAM protein abundance, reduced number of nucleoids, and increased nucleoid size.”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Discussion
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“Opa1 deficiency in C2C12 muscle cells caused increased NF-jB transcriptional activity, expression of NF-jB target genes, and production of IL-1b.”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Discussion
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“In all, we document that Opa1 is required for mtDNA stability and mitochondrial quality control.”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Discussion
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“our preliminary data indicate that mtDNA and TLR9 may be present in an intracellular compartment.”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Discussion
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“Analysis of the distribution of mtDNA and TOM20 (an outer mitochondrial membrane protein) revealed a complete colocalization of both markers in control muscle cells (Appendix Fig S4A and B).The two markers also showed close apposition in Opa1-deficient muscle cells (Appendix Fig S4A and B) suggesting that mtDNA and TOM20 were in the same compartment and that mtDNA is unlikely to be located in the”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Opa1 deficiency disrupts mitophagy completion in muscle cells
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“While control cells responded with a marked reduction in mitochondrial nucleoids upon 9-h incubation with CCCP, Opa1-deficient cells showed no mitophagic response (Fig 7B and C).”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Opa1 deficiency disrupts mitophagy completion in muscle cells
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- Rests on an assumption: CCCP induces mitochondrial depolarization and mitophagy in these cells.
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In the paper
“Opa1-depleted muscle also showed an impaired autophagy flux and treatment for 5 days with chloroquine caused a marked buildup of the autophagic protein LC3-II in muscles from control mice, whereas only a weak induction was detectable in Opa1 KO mice (Fig 7G and Appendix Fig S4F).”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Opa1 deficiency disrupts mitophagy completion in muscle cells
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- Rests on an assumption: Chloroquine effectively inhibits lysosomal degradation in muscle and muscle cells.
In the paper
“Control muscles responded to chloroquine by enhanced LC3-II abundance (Fig 7D, and Appendix Fig S4D) in keeping with prior data (Sebastian et al, 2016).In contrast, Opa1 ablated muscles only showed a weak non-significant increase in LC3-II (Fig 7D and Appendix Fig S4D).”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Opa1 deficiency disrupts mitophagy completion in muscle cells
What the sources say
- Not checked yetcites Sebastian et al, 2016 source
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- Rests on an assumption: Chloroquine effectively inhibits lysosomal degradation in muscle and muscle cells.
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In the paper
“Here, we report that Opa1 deficiency causes mitochondrial dysfunction both in skeletal muscle and in cultured muscle cells.”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Discussion
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In the paper
“However, here we report that Opa1 depletion causes mtDNA stress, but this occurs in the absence of leakage of mtDNA to the cytosol, and with no induction of interferon-stimulated genes, and instead it causes induction of NF-jB dependent on TLR9 activity.”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Discussion
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In the paper
“Inflammation was initially detected in 3-week-old Opa1 KO mice by enhanced IL-1b abundance and normal CD68 labeling (a marker of macrophage infiltration), whereas at greater ages (13 weeks of age), CD68 labeling was enhanced, thereby indicating macrophage infiltration.”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Discussion
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- Rests on an assumption: CD68 staining specifically marks pro-inflammatory macrophages in this muscle context.
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In the paper
“Thus, we have demonstrated that skeletal muscle-specific Opa1 ablation causes an inflammatory myopathy in mice, which is characterized by enhanced expression of NF-jB target genes, and increased circulating levels of pro-inflammatory cytokines IL-1b and IL-6.”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Discussion
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In the paper
“Triple labeling of mtDNA, LAMP1, and VPS4 in control and Opa1-deficient cells showed exclusion localization between mtDNA and LAMP1, and apposition of mtDNA and VPS4 signals (Appendix Fig S6C).”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Localization of mitochondrial DNA in Opa1-deficient muscle cells
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Interaction of TLR9 with mtDNA activates the nuclear factor kappa B (NF-jB) signaling and increases the expression of other pro-inflammatory cytokines such as tumor necrosis factor-a (TNF-a), interleukin (IL)-6, IL-1b (Julian et al, 2013;Yu & Bennett, 2014;Zhang et al, 2014).”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Introduction
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Interestingly, these patients show multiple mitochondrial DNA (mtDNA) deletions in muscles, which suggests a role of OPA1 on mtDNA stability.”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Introduction
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In all, our data indicate that Opa1-deficient muscle undergoes a primary inflammatory process characterized by NF-jB activation, followed by necrosis and then macrophage infiltration.”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Opa1 ablation causes inflammatory myopathy
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Taken together, our results reveal that Opa1 deficiency in muscle causes initial mitochondrial alterations that lead to TLR9 activation, and inflammation, which contributes to enhanced Fgf21 expression and to growth impairment.”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Mitochondrial fusion in mammalian cells is regulated by the proteins mitofusin 1 and mitofusin 2 (Mfn1 and Mfn2) and optic atrophy 1 (Opa1).”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Introduction
What the sources say
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“In addition to dominant optic atrophy, OPA1 mutations also cause a multi-systemic disorder called ADOA plus syndrome, which results in severe myopathy (Amati-Bonneau et al, 2008;Hudson et al, 2008;Zeviani, 2008).”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Introduction
What the sources say
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Thus, cytosolic mtDNA activates the DNA sensor cGAS and promotes STING-IRF3-dependent signaling (Rongvaux et al, 2014;White et al, 2014;West et al, 2015).”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Introduction
What the sources say
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“thereby revealing that the activation is a cell-autonomous process and independent of cell death.”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In all, these data indicate that Fgf21 mediates the metabolic alterations occurring in liver from Opa1 KO mice, but it is not involved in the reduced growth of Opa1 KO mice.”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Skeletal muscle-specific Opa1 ablation causes reduced body growth and premature death
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Opa1 participates in inner mitochondrial membrane fusion and cristae morphogenesis.”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Abstract
What the sources say
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Given the observation that Fgf21 causes resistance to GH (Inagaki et al, 2008)”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Skeletal muscle-specific Opa1 ablation causes reduced body growth and premature death
What the sources say
- Not checked yetcites Inagaki et al, 2008 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“MtDNA has been reported to activate immunity through two distinct pathways, namely Toll-like receptor 9 (TLR9; Zhang et al, 2010;Oka et al, 2012;Liu et al, 2015), and cGAS activation (White et al, 2014;West et al, 2015).”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Introduction
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“These data are consistent with the view that Opa1 deficiency in muscle causes global growth defects in conjunction with an altered Igf1 pathway (Wong et al, 2016).”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Discussion
What the sources say
- Not checked yetcites Wong et al, 2016 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“The use of mouse models has documented that overexpression of IL-6 causes reduced circulating levels of Igf1 and reduced growth which is rescued by blocking anti-IL-6 antibodies (De Benedetti et al, 1997).”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Discussion
What the sources say
- Not checked yetcites De Benedetti et al, 1997 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“On the basis of these data, we conclude that Opa1 deficiency causes muscle inflammation which is independent of muscle mass loss, that occurs before macrophage infiltration, and that it is mediated via activation of NF-jB.”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our data support the existence of mtDNA stress induced by Opa1 deficiency, which includes mtDNA loss and reduced nucleoids number.”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Opa1 deficiency has been reported to induce low mtDNA copy number and nucleoids abundance in human fibroblasts, which suggests that those alterations are not just restricted to muscle cells (Liao et al, 2017).”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Discussion
What the sources say
- Not checked yetcites Liao et al, 2017 source
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Interestingly, anti-inflammatory treatment also normalized FGF21 expression and its circulation levels, suggesting that the enhancement of the mitokine is downstream of inflammation.”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Given that high plasma concentrations of FGF21 have been observed to reduce growth hormone signaling, resulting in a marked growth defect (Inagaki et al, 2008)”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Discussion
What the sources say
- Not checked yetcites Inagaki et al, 2008 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
In the paper
“In addition, TNF-a, IL-1b, and IL-6 induce hepatic growth hormone resistance in mice (Zhao et al, 2014).”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Discussion
What the sources say
- Not checked yetcites Zhao et al, 2014 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
In the paper
“Inflammation has been reported to regulate growth (O' Connor et al, 2008).”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Discussion
What the sources say
- Not checked yetcites O' Connor et al, 2008 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
In the paper
“Growth inhibition is commonly observed in children with chronic inflammatory diseases such as juvenile idiopathic arthritis, chronic kidney disease, or chronic inflammatory bowel disease (Wong et al, 2016).”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Discussion
What the sources say
- Not checked yetcites Wong et al, 2016 source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In this study, we show that specific ablation of the mitochondrial fusion protein Opa1 in skeletal muscle results in whole body growth impairment, systemic inflammation, and premature death.”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In these patients, circulating concentrations of pro-inflammatory cytokines such as IL-1b and IL-6 are elevated (Kutukculer et al, 1998;Ji et al, 2002).”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Discussion
What the sources say
- Not checked yetcites Kutukculer et al, 1998 source
- Not checked yetcites Ji et al, 2002
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Based on data indicating that autophagy malfunction caused mtDNA-mediated inflammation (Nakahira et al, 2011;Oka et al, 2012)”
§ Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency > Opa1 deficiency disrupts mitophagy completion in muscle cells
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
The paper relies on this without support.
CD68 staining specifically marks pro-inflammatory macrophages in this muscle context.
“pro-inflammatory macrophages (stained for CD68)”
“a marker of macrophage infiltration”
The paper relies on this without support.
IL-1b labeling indicates inflammation in muscle.
“Highly positive labeling for IL-1b was already detected at 3 weeks in Opa1-deficient muscles”
The paper relies on this without support.
Ethidium bromide treatment depletes mtDNA without affecting other cellular processes relevant to NF-kB target gene expression.
“We depleted mtDNA in C2C12 muscle cells by chronic treatment with ethidium bromide (EtBr).”
The paper relies on this without support.
ODN2088 specifically antagonizes TLR9 in these cells.
“cells were treated with the TLR9 antagonist ligand ODN2088 or with the corresponding negative control.”
The paper relies on this without support.
Chloroquine effectively inhibits lysosomal degradation in muscle and muscle cells.
“treatment for 5 days with chloroquine caused a marked buildup of the autophagic protein LC3-II in muscles from control mice”
The paper relies on this without support.
CCCP induces mitochondrial depolarization and mitophagy in these cells.
“Mitochondrial autophagy was analyzed upon treatment of control of Opa1-deficient muscle cells with the depolarizing agent CCCP.”
The paper relies on this without support.
p62 accumulation reflects impaired autophagic flux in muscle.
“Time-course studies revealed significantly increased levels of p62”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Inhibition of the IMM profusion factor, OPA1, in muscle resulted in a similar but more severe phenotype than skeletal muscle MFN1 and MFN2 ablation [187, 192, 193].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [192]
In the citing paper
“When OPA1 was deleted during fetal development, animals died a few days after birth.”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [192]
In the citing paper
“Deletion of OPA1 in adult mice (3–5 months of age) resulted in a decrease of mtDNA, reduced respiratory complexes and supercomplexes content, and complex activity, respiration, and mitochondrial membrane potential.”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [192]
In the citing paper
“In contrast, muscle‐dependent systemic release of FGF21 increases with starvation, endoplasmic reticulum stress, mitochondrial dysfunction, obesity, mitochondrial myopathies, and aging.6, 13, 14, 15, 16, 17, 18, 19”
From Fibroblast growth factor 21 controls mitophagy and muscle mass (2019) · cites this paper as [16]
In the citing paper
“Moreover, we and others recently demonstrated that in a muscle‐specific OPA1 knockout animal model, characterized by mitochondrial dysfunction and by extensive muscle loss, the contribution of skeletal muscle to circulating FGF21 was predominant.15, 16, 18”
From Fibroblast growth factor 21 controls mitophagy and muscle mass (2019) · cites this paper as [16]
In the citing paper
“Opa1 deficiency reduces muscle fiber size, causes mitochondrial dysfunction and mitochondrial DNA release, and enhances FGF21, characterized by NF-κB activation, which contributes to muscle loss and weakness [61].”
From Exerkines and Sarcopenia: Unveiling the Mechanism Behind Exercise-Induced Mitochondrial Homeostasis (2025) · cites this paper as [61]
In the citing paper
“Taken altogether, the available literature clearly indicates that mitochondrial fusion proteins are essential for the maintenance of mitochondrial and skeletal muscle health.”
From Mitochondrial Dynamics and Mitophagy in Skeletal Muscle Health and Aging (2021) · cites this paper as [38]
In the citing paper
“Specific deletion of Opa1 in skeletal muscle leads to mitochondrial dysfunction, oxidative stress, endoplasmic reticulum (ER) stress, and inflammation [36,37,38].”
From Mitochondrial Dynamics and Mitophagy in Skeletal Muscle Health and Aging (2021) · cites this paper as [38]
In the citing paper
“Recently, the quality of mitochondria has emerged as important control process that regulates skeletal muscle function20–23.”
From Disuse-associated loss of the protease Lonp1 in muscle impairs mitochondrial function and causes reduced skeletal muscle mass and strength (2022) · cites this paper as [22]
In the citing paper
“proper maintenance of mitochondria dynamics, i.e. the balance between fission and fusion, is necessary for optimal muscle mitochondrial function and fitness20–23,43.”
From Disuse-associated loss of the protease Lonp1 in muscle impairs mitochondrial function and causes reduced skeletal muscle mass and strength (2022) · cites this paper as [22]
Citations
Cites
1 retracted
Mitochondrial DNA induces inflammation and increases TLR9/NF-κB expression in lung tissue
ZHANG, J.-Z., LIU, Z., LIU, J., REN, J.-X., & SUN, T.-S. (2014) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2014.1650 · Cited by 194
RetractedCirculating mitochondrial DAMPs cause inflammatory responses to injury
Zhang, Q., Raoof, M., Chen, Y., Sumi, Y., Sursal, T., Junger, W., Brohi, K., Itagaki, K., & Hauser, C. J. (2010) · Nature · doi:10.1038/nature08780 · Cited by 3,812
Fission and selective fusion govern mitochondrial segregation and elimination by autophagy
Twig, G., Elorza, A., Molina, A. J. A., Mohamed, H., Wikstrom, J. D., Walzer, G., Stiles, L., Haigh, S. E., Katz, S., Las, G., et al. (2008) · The EMBO Journal · doi:10.1038/sj.emboj.7601963 · Cited by 3,082
Self-citationNakahira, K., Haspel, J. A., Rathinam, V. A. K., Lee, S.-J., Dolinay, T., Lam, H. C., Englert, J. A., Rabinovitch, M., Cernadas, M., Kim, H. P., et al. (2011) · Nature Immunology · doi:10.1038/ni.1980 · Cited by 3,049
The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy
Lazarou, M., Sliter, D. A., Kane, L. A., Sarraf, S. A., Wang, C., Burman, J. L., Sideris, D. P., Fogel, A. I., & Youle, R. J. (2015) · Nature · doi:10.1038/nature14893 · Cited by 2,774
Mitochondrial DNA stress primes the antiviral innate immune response
West, A. P., Khoury-Hanold, W., Staron, M., Tal, M. C., Pineda, C. M., Lang, S. M., Bestwick, M., Duguay, B. A., Raimundo, N., MacDuff, D. A., et al. (2015) · Nature · doi:10.1038/nature14156 · Cited by 1,975
Inhibition of NF-κB by Sodium Salicylate and Aspirin
Kopp, E. B., & Ghosh, S. (1994) · Science · doi:10.1126/science.8052854 · Cited by 1,744
OPA1 Controls Apoptotic Cristae Remodeling Independently from Mitochondrial Fusion
Frezza, C., Cipolat, S., Martins de Brito, O., Micaroni, M., Beznoussenko, G. V., Rudka, T., Bartoli, D., Polishuck, R. S., Danial, N. N., De Strooper, B., et al. (2006) · Cell · doi:10.1016/j.cell.2006.06.025 · Cited by 1,673
The anti-inflammatory agents aspirin and salicylate inhibit the activity of IκB kinase-β
Yin, M.-J., Yamamoto, Y., & Gaynor, R. B. (1998) · Nature · doi:10.1038/23948 · Cited by 1,596
Delettre, C., Lenaers, G., Griffoin, J.-M., Gigarel, N., Lorenzo, C., Belenguer, P., Pelloquin, L., Grosgeorge, J., Turc-Carel, C., Perret, E., et al. (2000) · Nature Genetics · doi:10.1038/79936 · Cited by 1,446
Flagged first, then by citations
1 of the 65 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
The cell biology of mitochondrial membrane dynamics
Giacomello, M., Pyakurel, A., Glytsou, C., & Scorrano, L. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-0210-7 · Cited by 1,550
Mitochondrial dysfunction: mechanisms and advances in therapy
Yao, Z., Li, H., Liao, P., Chen, L., Pan, Y., Zheng, Y., Zhang, C., Liu, D., Zheng, M., & Gao, J. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01839-8 · Cited by 1,382
Mitochondrial DNA in inflammation and immunity
Riley, J. S., & Tait, S. W. G. (2020) · EMBO Reports · doi:10.15252/embr.201949799 · Cited by 910
Mitochondrial dynamics in adaptive and maladaptive cellular stress responses
Eisner, V., Picard, M., & Hajnóczky, G. (2018) · Nature Cell Biology · doi:10.1038/s41556-018-0133-0 · Cited by 622
Picca, A., Calvani, R., Coelho‐Júnior, H. J., Landi, F., Bernabei, R., & Marzetti, E. (2020) · Antioxidants · doi:10.3390/antiox9080647 · Cited by 465
Metadata
- Authors
- Rodríguez‐Nuevo, A., Díaz‐Ramos, A., Noguera, E., Díaz‐Sáez, F., Duran, X., Muñoz, J. P., Romero, M., Plana, N., Sebastián, D., Tezze, C., Romanello, V., Ribas, F., Seco, J., Planet, E., Doctrow, S. R., González, J., Borràs, M., Liesa, M., Palacín, M., Vendrell, J., Villarroya, F., Sandri, M., Shirihai, O., & Zorzano, A.
- Affiliations
- Instituto de Salud Carlos III (ES)
- Universitat de Barcelona (ES)
- Veneto Institute of Molecular Medicine (IT)
- Institute for Research in Biomedicine (ES)
- Boston University (US)
- Parc Científic de Barcelona (ES)
- University of California, Los Angeles (US)
- ORCID
- Venue
- The EMBO Journal
- Published
- 2018-04-06
- Volume
- 37
- Issue
- 10
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC5978453
- OpenAlex
- W2796990937
- Semantic Scholar
- f7306933c3e1fbdf751d9e98b5e032c8112b682d
- Cited by
- 207
- References
- 65
- Citations by year
- 2026: 11 · 2025: 24 · 2024: 26 · 2023: 32 · 2022: 24 · 2021: 40 · 2020: 30 · 2019: 13 · 2018: 6
- FWCI
- 7.87
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Padua Research Archive (University of Padova) (submittedVersion, other-oa)
- Funders
- “Ministerio de Educación y Cultura,” Spain
- Fundación Isabel Gemio
- FEDER y ASEM, Instituto de Salud Carlos III (PIE14/00045)
- INTERREG IV‐B‐SUDOE‐FEDER (SOE1/P1/E178)
- Ministerio de Economía y Competitividad (SAF2013‐40987R, SAF2016‐75246R)
- Generalitat de Catalunya (2014SGR48)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- OPA1, mitochondrial DNA, TLR9, muscle inflammation, skeletal muscle, NF-κB activation, FGF21, mitochondrial fusion, muscle fiber size, growth retardation, sodium salicylate
- MeSH terms
- Animals, Cells, Cultured, DNA, Mitochondrial, Female, Inflammation, Male, Muscular Diseases, Necrosis, Regeneration, Cytokines, Apoptosis, Mice, Knockout, Muscle, Skeletal, GTP Phosphohydrolases, Toll-Like Receptor 9
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-06, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
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