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Cited by 682Mitochondrial Function and PathologyMetabolism and Genetic DisordersGenomics and Rare Diseases

Mitochondrial DNA mutations and human disease

Open access
Tuppen, Helen A.L., Blakely, Emma L., Turnbull, Douglass M., Taylor, Robert W.·2010·Biochimica et Biophysica Acta (BBA) - Bioenergetics
DOI 10.1016/j.bbabio.2009.09.005
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Abstract

Mitochondrial disorders are a group of clinically heterogeneous diseases, commonly defined by a lack of cellular energy due to oxidative phosphorylation (OXPHOS) defects. Since the identification of the first human pathological mitochondrial DNA (mtDNA) mutations in 1988, significant efforts have been spent in cataloguing the vast array of causative genetic defects of these disorders. Currently, more than 250 pathogenic mtDNA mutations have been identified. An ever-increasing number of nuclear DNA mutations are also being reported as the majority of proteins involved in mitochondrial metabolism and maintenance are nuclear-encoded. Understanding the phenotypic diversity and elucidating the molecular mechanisms at the basis of these diseases has however proved challenging. Progress has been hampered by the peculiar features of mitochondrial genetics, an inability to manipulate the mitochondrial genome, and difficulties in obtaining suitable models of disease. In this review, we will first outline the unique features of mitochondrial genetics before detailing the diseases and their genetic causes, focusing specifically on primary mtDNA genetic defects. The functional consequences of mtDNA mutations that have been characterised to date will also be discussed, along with current and potential future diagnostic and therapeutic advances.

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes mitochondrial DNA (mtDNA) genetics, the clinical syndromes caused by primary mtDNA mutations, diagnostic approaches, experimental models, and therapeutic/prevention strategies. It emphasizes that more than 250 pathogenic mtDNA mutations are known, but heteroplasmy, threshold effects, genotype–phenotype heterogeneity, and limited disease models continue to complicate understanding and treatment.

Key findings

  • Since the first pathogenic mtDNA mutations were identified in 1988, over 250 pathogenic mtDNA mutations have been characterized; the mtDNA mutation rate is 10- to 17-fold higher than nuclear DNA. Prevalence estimates from North East England suggest 1 in 10,000 people have clinically manifesting mtDNA disease and a further 1 in 6000 are at risk; mutation frequencies include 0.14% for m.3243A>G and ∼0.2% for m.1555A>G.
  • Mitochondrial genetics is shaped by maternal inheritance, heteroplasmy/homoplasmy, a threshold effect typically around 60%–90% mutant mtDNA, mitotic segregation, clonal expansion, and a developmental bottleneck. Phenotype depends on mutation load and tissue, not simply on mutation size or location.
  • Common syndromes and mutations include MELAS (over 80% have m.3243A>G), LHON (three primary mutations account for at least 95% of cases; 50% of males versus 10% of females develop visual loss; recovery is 71% with m.14484T>C versus 25% with m.11778G>A), NARP/MILS (m.8993T>G; mutant load greater than 95% associates with childhood MILS), MERRF (m.8344A>G), KSS/Pearson syndrome (single large-scale deletions), and CPEO.
  • Diagnosis uses histochemistry (ragged red fibres, COX-deficient fibres), biochemical respiratory chain assays, and molecular testing (RFLP, long-range PCR, sequencing, microarrays). No effective treatment is currently available; exercise and gene therapy approaches are under investigation, and prevention strategies include prenatal diagnosis, preimplantation genetic diagnosis, pronuclear transfer, and spindle-chromosome transfer.

Methods

  • Narrative review; no primary data, systematic search strategy, or formal inclusion criteria are described. The evidence base is published literature on mtDNA genetics, clinical syndromes, diagnosis, functional characterization, and management.
  • The review synthesizes cited studies and databases, including MITOMAP, and discusses experimental models such as transmitochondrial cybrids, yeast models, and mouse models, as well as transcriptomic and proteomic investigations.
  • Main analysis is qualitative synthesis, with figures for genotype–phenotype correlations and criteria for assigning pathogenicity to novel mtDNA variants.

Limitations

  • The paper states that progress has been hampered by the peculiar features of mitochondrial genetics, an inability to manipulate the mitochondrial genome, and difficulties in obtaining suitable models of disease; it also notes that no effective therapies or cures are presently available and that exact prevalence is difficult to ascertain.
  • The text makes evident that this is a narrative review without systematic search or primary data, and that several areas remain debated or uncertain, including the exact mechanism of mtDNA replication, the mtDNA bottleneck, and the mechanism of mtDNA deletion formation.
  • Model-specific limitations are stated: cybrids often use aneuploid tumour cells and glycolytic host cells, and cybridization can alter the transcriptome; yeast are inherently homoplasmic and S. cerevisiae lack complex I; mouse mtDNA cannot be directly manipulated, requiring indirect approaches.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.bbabio.2009.09.005

Cites

261 of 261 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

0 of 127 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    mtDNA repair systems exist.

    “Although mtDNA repair systems do exist [51,52]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [51] Dianov, 2001, Base excision repair in nuclear and mitochondrial DNA, Prog. Nucleic Acid Res. Mol. Biol. source

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    • cites [52] de Souza-Pinto, 2009, Novel DNA mismatch-repair activity involving YB-1 in human mitochondria, DNA. Repair. (Amst) source

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  • Premisereasoning

    The mitochondrial genome has a very high mutation rate, 10- to 17-fold higher than that observed in nuclear DNA.

    “The mitochondrial genome has a very high mutation rate, 10-to 17-fold higher than that observed in nuclear DNA.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    The occurrence of multiple mtDNA deletions of varying lengths in affected tissues may be due to inherited mutations in nuclear genes involved in mtDNA maintenance and replication (e.g., POLG and PEO1) and mitochondrial nucleotide metabolism (e.g., SLC25A4).

    “The occurrence of multiple mtDNA deletions of varying lengths in affected tissues may be due to inherited mutations in nuclear genes, whose products are involved in mtDNA maintenance and replication (e.g., POLG and PEO1 encoding Twinkle) and mitochondrial nucleotide metabolism (e.g., SLC25A4) [88][89][90].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [88][89][90]

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  • Premisecitation

    A dominant mt-tRNA mutation, m.5545C>T in the MT-TW gene, was recently reported with levels of mutation at <25% in clinically affected tissues.

    “To complicate matters further, a dominant mt-tRNA mutation, m.5545C N T in the MT-TW gene, was recently reported with levels of mutation at b25% in clinically affected tissues [83].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [83] Sacconi, 2008, A functionally dominant mitochondrial DNA mutation, Hum. Mol. Genet. source

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  • Premisecitation

    The observation of rapid segregation in mammalian heteroplasmic mtDNA genotypes between generations, with a return to homoplasmy in some progeny, has suggested the existence of a mtDNA bottleneck during development.

    “The observation of a rapid segregation in mammalian heteroplasmic mtDNA genotypes between generations, with a return to homoplasmy in some progeny, has suggested the existence of a mtDNA bottleneck during development [67][68][69][70][71][72].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [67][68][69][70][71][72]

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  • Classified as probably not a substantial claim. 6
  • May combine two claims. 36

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    More than 250 pathogenic mtDNA mutations have been identified.

    “Currently, more than 250 pathogenic mtDNA mutations have been identified.”
    • Also stated in: § 3. Clinical features of human mtDNA disease · plain
      “Since then, over 250 pathogenic mtDNA mutations (point mutations and rearrangements) have been characterised [56]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [56] MITOMAP: A Human Mitochondrial Genome Database. http://www.mitomap.org. 2009.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    The onset of clinical symptoms, phenotypic variability, and variable penetrance of mitochondrial diseases are governed by a number of factors, including the threshold effect, mitotic segregation, clonal expansion, and a genetic bottleneck.

    “The onset of clinical symptoms, phenotypic variability, and variable penetrance of mitochondrial diseases are governed by a number of factors, including the threshold effect, mitotic segregation, clonal expansion, and a genetic bottleneck.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: In heteroplasmy, the ratio of wild-type to mutant mtDNA determines the onset of clinical symptoms.
    • Rests on an assumption: A minimum critical proportion of mutated mtDNAs is necessary before biochemical defects and tissue dysfunction become apparent.
    • Rests on an assumption: The threshold level varies for each mutation and differs amongst tissues, being lower in tissues highly dependent on OXPHOS metabolism than in tissues that can rely on anaerobic glycolysis.
    • Rests on an assumption: Typically, the threshold value is in the range of 60%-90% mutant to wild-type mtDNA.
    • Rests on an assumption: During mitosis, mitochondria are randomly segregated, and in heteroplasmic cells, the proportion of mutant mtDNA in the daughter cells can shift.
    • Rests on an assumption: If the mutant load exceeds the pathogenic threshold for that tissue, clinical expression of the disease can occur.
    • Rests on an assumption: Mutant mtDNA may be lost, particularly in fast-dividing tissues.

  • May combine two claims.

    Interpretationreasoning

    mtDNA repair systems are not sufficient to counteract the oxidative damage sustained by the mitochondrial genome due to its proximity to the RC complexes in the IMM and the ROS they generate, and protective histones are lacking.

    “they are not sufficient to counteract the oxidative damage sustained by the mitochondrial genome due to its proximity to the RC complexes in the IMM and the ROS they generate.Protective histones are also lacking.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Although the threshold level can partly explain the disease phenotypes observed in patients, an exact correlation between clinical severity and the proportion of mtDNA mutation is lacking.

    “Although the threshold level can partly explain the disease phenotypes observed in patients, an exact correlation between clinical severity and the proportion of mtDNA mutation is lacking [62].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [62] Wong, 2007, Diagnostic challenges of mitochondrial DNA disorders, Mitochondrion source

      Not checked in the free run.

    • Rests on an assumption: In heteroplasmy, the ratio of wild-type to mutant mtDNA determines the onset of clinical symptoms.
    • Rests on an assumption: A minimum critical proportion of mutated mtDNAs is necessary before biochemical defects and tissue dysfunction become apparent.
    • Rests on an assumption: The threshold level varies for each mutation and differs amongst tissues, being lower in tissues highly dependent on OXPHOS metabolism than in tissues that can rely on anaerobic glycolysis.
    • Rests on an assumption: Typically, the threshold value is in the range of 60%-90% mutant to wild-type mtDNA.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Clonal expansion refers to the preferential amplification of mtDNA mutations to a high level in post-mitotic tissues.

    “Clonal expansion refers to the preferential amplification of mtDNA mutations to a high level in post-mitotic tissues [64,65].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [64] Larsson, 1990, Progressive increase of the mutated mitochondrial DNA fraction in Kearns–Sayre syndrome, Pediatr. Res. source

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    • cites [65] Weber, 1997, A new mtDNA mutation showing accumulation with time and restriction to skeletal muscle, Am. J. Hum. Genet.

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    Premisecitation

    CPEO is typically caused by sporadic large-scale single deletions or multiple mtDNA deletions, although mtDNA point mutations are detected in some patients (e.g., m.3243A>G, m.12316G>A).

    “CPEO is typically caused by sporadic large-scale single deletions or multiple mtDNA deletions [119,120], although mtDNA point mutations are detected in some patients (e.g., m.3243A N G [121], m.12316G N A [122]).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [119] Moraes, 1989, Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns–Sayre syndrome, N. Engl. J. Med. source

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    • cites [120] Van Goethem, 2003, Progressive external ophthalmoplegia characterized by multiple deletions of mitochondrial DNA: unraveling the pathogenesis of human mitochondrial DNA instability and the initiation of a genetic classification, Neuromol. Med. source

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    • cites [121] Moraes, 1993, Atypical clinical presentations associated with the MELAS mutation at position 3243 of human mitochondrial DNA, Neuromuscul. Disord. source

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    • cites [122] Cardaioli, 2008, Chronic progressive external ophthalmoplegia: a new heteroplasmic tRNA(Leu(CUN)) mutation of mitochondrial DNA, J. Neurol. Sci. source

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    Premisecitation

    Single mtDNA deletions occur sporadically early in development, and the identical deletion is present in all cells within affected tissues.

    “Single mtDNA deletions occur sporadically early in development, and the identical deletion is present in all cells within affected tissues [87].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [87] Chen, 1995, Rearranged mitochondrial genomes are present in human oocytes, Am. J. Hum. Genet.

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    Premisecitation

    Leigh syndrome is due to severe failure of oxidative metabolism and can be due to a variety of different genetic defects affecting either the mitochondrial (e.g., m.8993T>C/G, m.10158T>C, m.10191T>C) or nuclear genome (e.g., SURF1 gene).

    “Leigh syndrome is due to severe failure of oxidative metabolism and can be due to a variety of different genetic defects affecting either the mitochondrial (e.g., m.8993T N C/G, m.10158T N C, m.10191T N C) or nuclear genome (e.g., SURF1 gene) [105].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [105] Finsterer, 2008, Leigh and Leigh-like syndrome in children and adults, Pediatr. Neurol. source

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    Premisecitation

    Most mtDNA deletions share common features: they mainly occur between the origins of replication, O_H and O_L, and are typically flanked by short direct repeats.

    “They mainly occur between the origins of replication, O H and O L , and are typically flanked by short direct repeats [94,95].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [94] Bua, 2006, Mitochondrial DNA-deletion mutations accumulate intracellularly to detrimental levels in aged human skeletal muscle fibers, Am. J. Hum. Genet. source

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    • cites [95] Samuels, 2004, Two direct repeats cause most human mtDNA deletions, Trends Genet. source

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    Premisecitation

    The majority of mtDNA rearrangement mutations are large-scale deletions, which vary in size from 1.3 to 8 kb and span several genes.

    “The majority of mtDNA rearrangement mutations are large-scale deletions, which vary in size from 1.3 to 8 kb and span several genes [86].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [86] Schon, 1989, A direct repeat is a hotspot for large-scale deletion of human mitochondrial DNA, Science source

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  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    A mammalian in vivo model system is ultimately necessary for answering questions about mtDNA biology, mitochondrial disease pathogenesis, and tissue specificity.

    “Whilst cybrids and yeast have helped to further our current understanding of mitochondrial genetics and the molecular mechanisms of disease, a mammalian in vivo model system is ultimately necessary for answering the many questions regarding mtDNA biology, mitochondrial disease pathogenesis and tissue specificity that still remain.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Cybrids have identified the first mt-tRNA suppressor mutation (m.12300G N A in MT-L2) and the first functionally dominant mt-tRNA mutation (m.5545C N T in MT-TW).

    “In addition, these cell models have challenged our established criteria for pathogenicity with the identification of the first mt-tRNA suppressor mutation, m.12300G N A in MT-L2 [154], and the first functionally dominant mt-tRNA mutation, m.5545C N T in MT-TW [155].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [154] El Meziane, 1998, A tRNA suppressor mutation in human mitochondria, Nat. Genet. source

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    • cites [155] Khan, 2007, Cell and animal models of mtDNA biology: progress and prospects, Am. J. Physiol., Cell Physiol. source

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    Premisecitation

    A global decrease in the activity of COX is usually suggestive of a nuclear mutation in an ancillary protein required for COX assembly such as SURF1 but can be associated with some homoplasmic mt-tRNA defects.

    “A global decrease in the activity of COX is usually suggestive of a nuclear mutation in an ancillary protein required for COX assembly such as SURF1 but can be associated with some homoplasmic mt-tRNA defects [77,78].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [77] McFarland, 2002, Multiple neonatal deaths due to a homoplasmic mitochondrial DNA mutation, Nat. Genet. source

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    • cites [78] Taylor, 2003, A homoplasmic mitochondrial transfer ribonucleic acid mutation as a cause of maternally inherited hypertrophic cardiomyopathy, J. Am. Coll. Cardiol. source

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    Premisecitation

    The assessment of m.3243A>G mutation load in urinary sediments not only provides a correlate with the level in muscle but also has proven to be an accurate indicator of clinical outcome for these patients.

    “The assessment of m.3243A N G mutation load in urinary sediments not only provides a correlate with the level in muscle but also has proven to be an accurate indicator of clinical outcome for these patients [138].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [138] Whittaker, 2009, Urine heteroplasmy is the best predictor of clinical outcome in the m.3243A>G mtDNA mutation, Neurology source

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  • May combine two claims.

    Premisereasoning

    Cybrids allow selected mtDNA sequences to be expressed against fixed nuclear backgrounds, enabling study of genetic origin, functional and physiological consequences of heteroplasmy, and molecular mechanisms of mtDNA mutations.

    “By allowing selected mtDNA sequences to be expressed against fixed nuclear backgrounds, not only can cybrids be employed for establishing and/or confirming the genetic origin of a mitochondrial disorder, but they can also provide a controlled environment in which to study both the functional and physiological consequences of varying levels of heteroplasmy of specific mtDNA mutations as well as the”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    It is unlikely that a reduced respiration rate is solely responsible for the variability of mitochondrial disorder phenotypes; additional molecular mechanisms must contribute to the development and clinical presentation of disease.

    “Consequently, it is unlikely that a reduced respiration rate is solely responsible for this variability, but rather additional molecular mechanisms must also contribute to the development and clinical presentation of disease.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Clinical phenotypes of mitochondrial disorders are extremely heterogeneous.
    • Rests on an assumption: Pathogenic mtDNA mutations invariably result in a general defect in mitochondrial respiration that leads to a reduced ability to produce cellular ATP.

  • May combine two claims.

    Premisecitation

    DNA delivered to yeast mitochondria via biolistic transformation incorporates only by homologous recombination, allowing controlled introduction of mutations at any desired position in yeast mtDNA genes.

    “Most importantly, this can be achieved in a highly controlled fashion as DNA delivered to mitochondria via biolistic transformation can only incorporate into the mitochondrial genome by homologous recombination [160].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [160] Bonnefoy, 2001, Genetic transformation of Saccharomyces cerevisiae mitochondria, Methods Cell Biol. source

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    Premisecitation

    Yarrowia lipolytica possesses a vital proton-pumping NADH:ubiquinone oxidoreductase and has enabled important structural and functional analyses of mitochondrial complex I.

    “However, the introduction over the past decade of an alternative model, the obligate aerobic yeast Yarrowia lipolytica, which possesses a vital proton-pumping NADH:ubiquinone oxidoreductase, has enabled important structural and functional analyses of mitochondrial complex I [168].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [168] Kerscher, 2004, Application of the yeast Yarrowia lipolytica as a model to analyse human pathogenic mutations in mitochondrial complex I (NADH:ubiquinone oxidoreductase), Biochim. Biophys. Acta source

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    Premisecitation

    The 'Mito-mice' model harbours high levels of a single heteroplasmic mtDNA deletion and shows multiple symptoms including myopathy, cardiomyopathy, renal failure, anaemia, deafness, lactic acidosis, a mosaic pattern of COX deficiency, and a shortened life-span.

    “Additional transmitochondrial mouse models, showing signs of mitochondrial dysfunction and capable of transmitting mtDNA mutations to subsequent generations, have since been established, including the 'Mito-mice' model that harbours high levels of a single heteroplasmic mtDNA deletion and shows a multitude of symptoms including myopathy, cardiomyopathy, renal failure, anaemia, deafness, lactic”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [172] Inoue, 2000, Generation of mice with mitochondrial dysfunction by introducing mouse mtDNA carrying a deletion into zygotes, Nat. Genet. source

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    • cites [173] Nakada, 2004, Accumulation of pathogenic DeltamtDNA induced deafness but not diabetic phenotypes in mito-mice, Biochem. Biophys. Res. Commun. source

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  • May combine two claims.

    Premisecitation

    S. cerevisiae are inherently homoplasmic, precluding threshold studies, but severity of yeast respiratory phenotypes can be modulated by studying mt-tRNA mutations in different nuclear contexts.

    “Also, S. cerevisiae are inherently homoplasmic, thus precluding threshold studies, although it is possible to modulate the severity of yeast respiratory phenotypes by studying mt-tRNA mutations in different nuclear contexts [163,164].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [163] De Luca, 2006, Mutations in yeast mt tRNAs: specific and general suppression by nuclear encoded tRNA interactors, Gene source

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    • cites [164] Montanari, 2008, Yeast as a model of human mitochondrial tRNA base substitutions: investigation of the molecular basis of respiratory defects, Rna source

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    Premisecitation

    The progression of LHON seems to depend upon the responsible mutation with 71% of patients with the m.14484T>C mutation showing some recovery, compared to 25% with m.11778G>A.

    “The progression of the disease seems to depend upon the responsible mutation with 71% of patients with the m.14484T N C mutation showing some recovery, compared to 25% with m.11778G N A [125].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [125] Riordan-Eva, 1995, The clinical features of Leber's hereditary optic neuropathy defined by the presence of a pathogenic mitochondrial DNA mutation, Brain source

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    Premisecitation

    Cybrids harbouring the homoplasmic MT-TV m.1624C N T mutation lack the marked respiratory defect despite retaining a striking reduction in mt-tRNA Val steady-state levels, whereas the mutation caused a profound metabolic defect in skeletal and cardiac muscle in vivo.

    “For example, cybrids harbouring the homoplasmic MT-TV m.1624C N T mutation, which caused a profound metabolic defect in skeletal and cardiac muscle, with low complex I and IV activities, and resulted in multiple neonatal deaths [159], were found to lack the marked respiratory defect despite retaining a striking reduction in mt-tRNA Val steady-state levels [159].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [159] Rorbach, 2008, Overexpression of human mitochondrial valyl tRNA synthetase can partially restore levels of cognate mt-tRNAVal carrying the pathogenic C25U mutation, Nucleic Acids Res. source

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    Premisecitation

    Increased ROS production has been described in neuronal NT2 cybrid cells containing m.3460G N A and m.11778G N A LHON mutations, in lymphocytes with m.8993T N C and m.8993T N G NARP mutations, and in chimeric m.3243A N G mice.

    “Increased ROS production has been described in neuronal NT2 cybrid cells containing m.3460G N A and m.11778G N A LHON mutations [187], in lymphocytes with m.8993T N C and m.8993T N G NARP mutations [188] and more recently in the chimeric m.3243A N G mice mentioned previously [175].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [187] Wong, 2002, Differentiation-specific effects of LHON mutations introduced into neuronal NT2 cells, Hum. Mol. Genet. source

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    • cites [188] Baracca, 2007, Biochemical phenotypes associated with the mitochondrial ATP6 gene mutations at nt8993, Biochim. Biophys. Acta source

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    • cites [175] Li, 2008, Increased ROS generation and SOD activity in heteroplasmic tissues of transmitochondrial mice with A3243G mitochondrial DNA mutation, Genet. Mol. Res. source

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    Premisecitation

    Normal levels of ROS were measured in POLG1 mutator mice, which eventually accumulate sufficient mtDNA mutations to cause severe OXPHOS deficiency.

    “Conversely, normal levels of ROS were measured in the POLG1 mutator mice, which eventually accumulate sufficient mtDNA mutations to cause severe OXPHOS deficiency [189].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [189] Trifunovic, 2005, Somatic mtDNA mutations cause aging phenotypes without affecting reactive oxygen species production, Proc. Natl. Acad. Sci. U. S. A. source

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  • May combine two claims.

    Premisenone given

    Biochemical effects of mtDNA mutations are invariably characterised by lower cellular respiration, compromised RC complex activity, and reduced ATP synthesis.

    “Biochemical effects of mtDNA mutations have been well described in all experimental systems and are invariably characterised by lower cellular respiration, compromised RC complex activity, and reduced ATP synthesis.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    m.5874T N C and m.5877C N T transitions decrease aminoacylation.

    “and the mt-tRNA Tyr m.5874T N C and m.5877C N T transitions [204].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [204] Bonnefond, 2008, Decreased aminoacylation in pathology-related mutants of mitochondrial tRNATyr is associated with structural perturbations in tRNA architecture, RNA source

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    Premisecitation

    No increase in programmed cell death was identified in POLG1 mutator mice, contrary to double TFAM knockout mice where substantial apoptosis occurred at embryonic day 9.5.

    “Furthermore, no increase in programmed cell death was identified in this mouse model, contrary to a double TFAM knockout mouse model in which substantial apoptosis occurred at embryonic day 9.5 [179,190].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [179] Wang, 1999, Dilated cardiomyopathy and atrioventricular conduction blocks induced by heart-specific inactivation of mitochondrial DNA gene expression, Nat. Genet. source

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    • cites [190] Wang, 2001, Increased in vivo apoptosis in cells lacking mitochondrial DNA gene expression, Proc. Natl. Acad. Sci. U. S. A. source

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    Premisecitation

    PNAs colocalised to mitochondria in intact cells but were not able to cross the inner mitochondrial membrane.

    “However, although PNAs colocalised to mitochondria in intact cells, they were not able to cross the IMM.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [234] Taylor, 1997, Selective inhibition of mutant human mitochondrial DNA replication in vitro by peptide nucleic acids, Nat. Genet. source

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    Premisecitation

    Shared transcriptional consequences of mitochondrial dysfunction include inhibition of ubiquitin-mediated protein degradation and mitochondrial/nuclear ribosomal protein synthesis, and activation of the unfolded protein response.

    “Other shared transcriptional consequences of mitochondrial dysfunction include inhibition of both ubiquitin-mediated protein degradation and mitochondrial and nuclear ribosomal protein synthesis [214,215], as well as activation of the unfolded protein response [215,216].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [214] Jahangir Tafrechi, 2005, Distinct nuclear gene expression profiles in cells with mtDNA depletion and homoplasmic A3243G mutation, Mutat. Res. source

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    • cites [215] Alemi, 2007, Mitochondrial DNA deletions inhibit proteasomal activity and stimulate an autophagic transcript, Free Radic. Biol. Med. source

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    • cites [216] Cortopassi, 2006, Mitochondrial disease activates transcripts of the unfolded protein response and cell cycle and inhibits vesicular secretion and oligodendrocyte-specific transcripts, Mitochondrion source

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    Premisecitation

    m.9205delTA eliminates the MT-ATP6 gene stop codon, places MT-CO3 immediately in frame, and causes a marked decrease in RNA14 steady-state levels.

    “Moreover, the nature of the mtDNA mutations, in particular the m.9205delTA deletion, which eliminates the MT-ATP6 gene stop codon, placing MT-CO3 immediately in frame, and causes a marked decrease in RNA14 (MT-ATP8 and -6-encoding bicistronic transcript) steady-state levels [81]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [81] Temperley, 2003, Investigation of a pathogenic mtDNA microdeletion reveals a translation-dependent deadenylation decay pathway in human mitochondria, Hum. Mol. Genet. source

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    Premisecitation

    Muscle conditioning enhanced ATP levels, delayed disease onset, and increased life expectancy in COX10 knockout mice.

    “Muscle conditioning enhanced ATP levels, delayed disease onset, and increased life expectancy in these mice.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [231] Wenz, 2009, Endurance exercise is protective for mice with mitochondrial myopathy, J. Appl. Physiol. source

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    Premisecitation

    Endurance training for up to 14 weeks improves OXPHOS function, but does not shift mutated mtDNA levels in muscle, and cessation causes loss of physiological adaptations.

    “Well tolerated and safe, endurance training for up to 14 weeks has been found to improve OXPHOS function, although no concomitant shift in mutated mtDNA levels in muscle has been observed and cessation in training does cause a loss of the physiological adaptations [228][229][230].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [228] Taivassalo, 2005, Exercise and training in mitochondrial myopathies, Med. Sci. Sports Exerc. source

      Not checked in the free run.

    • cites [229] Jeppesen, 2006, Aerobic training is safe and improves exercise capacity in patients with mitochondrial myopathy, Brain source

      Not checked in the free run.

    • cites [230] Taivassalo, 2006, Endurance training and detraining in mitochondrial myopathies due to single large-scale mtDNA deletions, Brain source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Imported tRNA Lys molecules are correctly aminoacylated, participate in mitochondrial translation, and partially rescue mitochondrial functions.

    “Imported tRNA Lys molecules are correctly aminoacylated, able to participate in mitochondrial translation, and partially rescue mitochondrial functions [242].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [242] Kolesnikova, 2004, Nuclear DNA-encoded tRNAs targeted into mitochondria can rescue a mitochondrial DNA mutation associated with the MERRF syndrome in cultured human cells, Hum. Mol. Genet. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    MitoCarta consists of 1098 identified proteins.

    “The most recent mammalian mitochondrial compendium (MitoCarta) consists of 1098 identified proteins [209].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [209] Pagliarini, 2008, A mitochondrial protein compendium elucidates complex I disease biology, Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Overexpression of valyl and leucyl synthetases increases steady-state levels of mutant mt-tRNA Val and mt-tRNA Leu(UUR), respectively.

    “Furthermore, two recent studies have demonstrated an increase in mutant mt-tRNA Val [159] and mt-tRNA Leu(UUR) [166] steady-state levels following overexpression of the valyl and leucyl synthetases, respectively.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [159] Rorbach, 2008, Overexpression of human mitochondrial valyl tRNA synthetase can partially restore levels of cognate mt-tRNAVal carrying the pathogenic C25U mutation, Nucleic Acids Res. source

      Not checked in the free run.

    • cites [166] Park, 2008, Overexpressed mitochondrial leucyl-tRNA synthetase suppresses the A3243G mutation in the mitochondrial tRNA(Leu(UUR)) gene, Rna source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Twelve-week resistance training in patients with single, large-scale mtDNA deletions increases satellite cell number and improves muscular strength and oxidative capacity, evidenced by decreased COX-negative fibres.

    “Twelve-week resistance training studies in patients with single, large-scale mtDNA deletions have been demonstrated to increase satellite cell number with concomitant improvements in muscular strength and oxidative capacity evidenced by a decrease in the proportion of COX-negative fibres [233].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [233] Murphy, 2008, Resistance training in patients with single, large-scale deletions of mitochondrial DNA, Brain source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AOX was well tolerated and transfectants displayed remarkable cyanide resistance to mitochondrial metabolite oxidation.

    “Indeed, AOX was well tolerated and transfectants displayed remarkable levels of cyanide resistance to mitochondrial metabolite oxidation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [247] Hakkaart, 2006, Allotopic expression of a mitochondrial alternative oxidase confers cyanide resistance to human cell respiration, EMBO Rep. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In heteroplasmic mice, heteroplasmy levels are almost identical between the ooplasm and polar body of the mature oocyte and also between individual blastomeres.

    “However, studies in heteroplasmic mice have demonstrated almost identical levels of heteroplasmy between the ooplasm and polar body of the mature oocyte and also between individual blastomeres [250].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [250] Dean, 2003, Prospect of preimplantation genetic diagnosis for heritable mitochondrial DNA diseases, Mol. Hum. Reprod. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Pronuclear transfer is presently being investigated in abnormally fertilised human embryos.

    “An alternative approach involving pronuclear transfer, the transfer of the pronuclei from a fertilised zygote of a mother with mtDNA disease to an enucleated zygote from a healthy donor female, is presently being investigated in abnormally fertilised human embryos (Turnbull et al., unpublished data).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Turnbull et al., unpublished data

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Spindle-chromosome complex transfer from a mature primate oocyte to an enucleated primate egg successfully produced healthy offspring, in which spindle donor mtDNA was not detected.

    “Recently, spindle-chromosome complex transfer from a mature primate oocyte to an enucleated primate egg successfully produced healthy offspring, in which, importantly, spindle donor mtDNA was not detected [252].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [252] Tachibana, 2009, Mitochondrial gene replacement in primate offspring and embryonic stem cells, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AOX was successfully transfected and targeted to the inner mitochondrial membrane in human cultured cells.

    “Furthermore, an encouraging strategy for the potential rescue of mitochondrial COX defects may soon be possible following the successful transfection and IMM targeting in human cultured cells of the sea squirt Ciona intestinalis cyanide-insensitive alternative oxidase (AOX) [247].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [247] Hakkaart, 2006, Allotopic expression of a mitochondrial alternative oxidase confers cyanide resistance to human cell respiration, EMBO Rep. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Xenotopic expression of CrATP6 in human cybrids with m.8993T N G resulted in moderately improved ATP production and fully recovered cellular viability.

    “Similarly, xenotopic expression of the green alga Chlamydomonas reinhardtii ATPase 6 (CrATP6) in human cybrid cells harbouring the m.8993T N G mutation resulted in moderately improved ATP production whilst cellular viability was fully recovered [246].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [246] Ojaimi, 2002, An algal nucleus-encoded subunit of mitochondrial ATP synthase rescues a defect in the analogous human mitochondrial-encoded subunit, Mol. Biol. Cell source

      Not checked in the free run.

42 of 42

  • The paper relies on this without support.

    In heteroplasmy, the ratio of wild-type to mutant mtDNA determines the onset of clinical symptoms.

    “In the presence of heteroplasmy, the ratio of wild-type to mutant mtDNA determines the onset of clinical symptoms.”

  • The paper relies on this without support.

    A minimum critical proportion of mutated mtDNAs is necessary before biochemical defects and tissue dysfunction become apparent.

    “A minimum critical proportion of mutated mtDNAs is necessary before biochemical defects and tissue dysfunction become apparent.”

  • The paper relies on this without support.

    The threshold level varies for each mutation and differs amongst tissues, being lower in tissues highly dependent on OXPHOS metabolism than in tissues that can rely on anaerobic glycolysis.

    “This threshold level varies for each mutation and differs amongst tissues, being lower in tissues highly dependent on OXPHOS metabolism than in tissues that can rely on anaerobic glycolysis.”

  • The paper relies on this without support.

    Typically, the threshold value is in the range of 60%-90% mutant to wild-type mtDNA.

    “Typically, the threshold value is in the range of 60%-90% mutant to wild-type mtDNA.”

  • The paper relies on this without support.

    During mitosis, mitochondria are randomly segregated, and in heteroplasmic cells, the proportion of mutant mtDNA in the daughter cells can shift.

    “During mitosis, mitochondria are randomly segregated, and in heteroplasmic cells, the proportion of mutant mtDNA in the daughter cells can thus shift.”

  • The paper relies on this without support.

    If the mutant load exceeds the pathogenic threshold for that tissue, clinical expression of the disease can occur.

    “Should the mutant load exceed the pathogenic threshold for that tissue, clinical expression of the disease can occur.”

  • The paper relies on this without support.

    Mutant mtDNA may be lost, particularly in fast-dividing tissues.

    “Conversely, mutant mtDNA may be lost, particularly in fast-dividing tissues.”

  • The paper relies on this without support.

    MtDNA point mutations are usually maternally inherited.

    “MtDNA point mutations are usually maternally inherited.”

  • The paper relies on this without support.

    More than half of disease-related point mutations reported are located within mt-tRNA genes.

    “However, more than half of disease-related point mutations reported are located within mt-tRNA genes.”

  • The paper relies on this without support.

    Point mutations in mitochondrial protein-coding genes specifically affect the function of the RC complex to which the corresponding protein belongs, whereas mt-tRNA mutations may impair overall mitochondrial translation by reducing the availability of functional mt-tRNAs.

    “Phenotypically, point mutations in mitochondrial protein-coding genes specifically affect the function of the RC complex to which the corresponding protein belongs, whereas mt-tRNA mutations may impair overall mitochondrial translation by reducing the availability of functional mt-tRNAs.”

  • The paper relies on this without support.

    Point mutations are mostly heteroplasmic, displaying considerable clinical heterogeneity, and are considered highly recessive.

    “Point mutations are mostly heteroplasmic, displaying considerable clinical heterogeneity, and are considered highly recessive.”

  • The paper relies on this without support.

    LHON is usually due to a homoplasmic mtDNA mutation and all maternal offspring will inherit the mutation; however, whilst 50% of males will be affected, only 10% of females will develop visual loss.

    “LHON is usually due to a homoplasmic mtDNA mutation and all maternal offspring will inherit the mutation; however, whilst 50% of males will be affected, only 10% of females will develop visual loss.”

  • The paper relies on this without support.

    The clinical syndromes associated with mtDNA mutations are extremely variable and patients can present at any stage in life.

    “The clinical syndromes associated with mtDNA mutations are extremely variable and patients can present at any stage in life.”

  • The paper relies on this without support.

    On the whole, the age of onset reflects the level of mutation and the severity of the biochemical defect, but other factors (presumably nuclear genetic or environmental) also affect the expression of disease.

    “On the whole, the age of onset reflects the level of mutation and the severity of the biochemical defect, but other factors (presumably nuclear genetic or environmental) also effect the expression of disease.”

  • The paper relies on this without support.

    Many, but not all, patients with mtDNA disease show histological and histochemical changes in affected tissue, indicative of RC dysfunction.

    “Many, but not all, patients with mtDNA disease show histological and histochemical changes in affected tissue, indicative of RC dysfunction.”

  • The paper relies on this without support.

    Some mutations—mtDNA rearrangements and certain mtDNA point mutations—are only present in clinically affected tissues, necessitating the work-up on postmitotic (muscle) DNA samples.

    “Some mutations-mtDNA rearrangements and certain mtDNA point mutations-are only present in clinically affected tissues, necessitating the work-up on postmitotic (muscle) DNA samples.”

  • The paper relies on this without support.

    Due to its small size, screening the entire mitochondrial genome can be undertaken relatively easily to identify rare or novel mtDNA mutations in patients with suspected mtDNA disease.

    “Due to its small size, screening the entire mitochondrial genome can be undertaken relatively easily to identify rare or novel mtDNA mutations in patients with suspected mtDNA disease.”

  • The paper relies on this without support.

    Clinical phenotypes of mitochondrial disorders are extremely heterogeneous.

    “The clinical phenotypes of mitochondrial disorders are however extremely heterogeneous.”

  • The paper relies on this without support.

    Engineering mtDNA is problematic due to its polyploidy, inaccessibility within a double-membraned organelle, and apparent lack of, or minimal, recombination, which have prevented the successful transfection of autonomously replicating foreign DNA plasmids or modified mtDNA into mitochondria to date.

    “Firstly, engineering mtDNA is problematic due to its polyploidy, inaccessibility within a double-membraned organelle, and apparent lack of, or minimal, recombination, which have prevented the successful transfection of autonomously replicating foreign DNA plasmids or modified mtDNA into mitochondria to date.”

  • The paper relies on this without support.

    Most cybrid models are generated using aneuploid tumour cells.

    “Most cybrid models are generated using aneuploid tumour cells.”

  • The authors state this as an assumption.

    Aneuploidy can affect the stoichiometry of nuclear- and mitochondrial-encoded RC subunits, thus interfering with genotype-phenotype relationships.

    “however, it is reasonable to assume that it can affect the stoichiometry of nuclear-and mitochondrial-encoded RC subunits, thus interfering with genotype-phenotype relationships.”

  • The paper relies on this without support.

    Tumour cells are largely glycolysis-dependent, relying little on OXPHOS for generating the majority of their energy requirements.

    “On a similar note, tumour cells are largely glycolysis-dependent, relying little on OXPHOS for generating the majority of their energy requirements.”

  • The paper relies on this without support.

    mtDNA disorders typically occur in highly aerobic cells.

    “In contrast, mtDNA disorders typically occur in highly aerobic cells.”

  • The paper relies on this without support.

    S. cerevisiae is currently the only known organism in which mitochondrial genetic transformation is possible.

    “Saccharomyces cerevisiae is currently the only known organism in which mitochondrial genetic transformation is possible.”

  • The paper relies on this without support.

    S. cerevisiae can survive in the complete absence of functional mtDNA.

    “Furthermore, in view of the ability of S. cerevisiae to survive in the complete absence of functional mtDNA, the study of very severe mitochondrial defects is possible.”

  • The paper relies on this without support.

    Not all human mt-tRNAs share strong homology with yeast mt-tRNAs.

    “Not all human mt-tRNAs share strong homology with yeast mt-tRNAs.”

  • The paper relies on this without support.

    Fermentative yeast such as S. cerevisiae lack complex I.

    “Finally, fermentative yeast such as S. cerevisiae lack complex I.”

  • The paper relies on this without support.

    It is not possible to directly manipulate the mouse mitochondrial genome.

    “As it is not possible to directly manipulate their mitochondrial genome, researchers have been forced to adopt more ingenious and indirect ways of engineering mouse mtDNA.”

  • The paper relies on this without support.

    No effective treatment options are currently available for patients with mitochondrial dysfunction, except in rare cases where surgery or transplant may be indicated.

    “Despite considerable advances over the last decade in our understanding of mitochondrial genetics and function and the pathogenesis of mtDNA diseases, no effective treatment options are currently available for patients with mitochondrial dysfunction, except in rare cases where surgery or transplant may be indicated.”

  • The paper relies on this without support.

    Satellite cells proliferate in response to damage caused by concentric or eccentric muscular contractions.

    “Undifferentiated myogenic cells, satellite cells, are known to proliferate in response to damage caused by concentric (shortening) or eccentric (lengthening) muscular contractions.”

  • The paper relies on this without support.

    Pathogenic mtDNA mutations invariably result in a general defect in mitochondrial respiration that leads to a reduced ability to produce cellular ATP.

    “Pathogenic mtDNA mutations invariably result in a general defect in mitochondrial respiration that leads to a reduced ability to produce cellular ATP.”

  • The paper relies on this without support.

    No effective therapies or cures are presently available for patients with mtDNA disease.

    “Disappointingly, no effective therapies or cures are presently available for patients with mtDNA disease.”
32 of 32

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?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • LHON mutation is given in opposite directions

    Minor

    The LHON section identifies the mutation at position 11778 as G to A, but later in the same paragraph calls it A to G.

  • Figure 1's list of 13 polypeptides omits ND5 and ND6

    Minor

    The figure caption presents its list as the 13 mtDNA-encoded respiratory-chain polypeptides, but the listed names account for only 11. Elsewhere the paper identifies MT-ND6 as an mtDNA gene, which is absent from that list; it also discusses MT-ND5.

2 of 2

Cites

1 retracted

Flagged first, then by citations

11 of the 272 references couldn’t be matched to a known paper.

Research works printed but not linked: 2

  1. Chen, 1995, Rearranged mitochondrial genomes are present in human oocytes, Am. J. Hum. Genet., 57, 239
  2. Oefner, 1995, Comparative DNA sequencing by high-performance liquid chromatography, Am. J. Hum. Genet., 57, A266

Cited by

Sorted by citations

Related

Authors
Tuppen, H. A. L., Blakely, E. L., Turnbull, D. M., & Taylor, R. W.
Affiliations
Newcastle University (GB)
Corresponding author
Taylor, Robert W.
ORCID
Venue
Biochimica et Biophysica Acta (BBA) - Bioenergetics
Publisher
Elsevier BV
Published
2010-02
Volume
1797
Issue
2
Pages
113-128
ISSN
0005-2728 (ISSN-L)
DOI
10.1016/j.bbabio.2009.09.005
OpenAlex
W1997422422
Semantic Scholar
b52cea89f7d29e4137fb6e7175963cf0d992f736
Cited by
676
References
272
Citations by year
2026: 19 · 2025: 34 · 2024: 41 · 2023: 32 · 2022: 35 · 2021: 50 · 2020: 51 · 2019: 46 · 2018: 81 · 2017: 44 · 2016: 49 · 2015: 32 · 2014: 24 · 2013: 33 · 2012: 38
FWCI
2.63
Type
journal article
Language
en
Open access
Licence
Locations
  • Biochimica et Biophysica Acta (BBA) - Bioenergetics (publishedVersion)
  • PubMed (publishedVersion)
  • Newcastle University ePrints (Newcastle Univesity)
Funders
  • Wellcome Trust (074454)
  • Sparks
  • Muscular Dystrophy UK
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Keywords
mitochondrial DNA mutations, mitochondrial disease, oxidative phosphorylation defects, mitochondrial genetics, nuclear-encoded mitochondrial proteins, mitochondrial disease diagnosis, mitochondrial disease therapy, disease models
MeSH terms
DNA, Mitochondrial, Humans, Mutation, Mitochondrial Diseases

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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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