The DOI matches its Crossref record; 261 of the 272 references it cites were found in a registry or an index; 1 of the 127 sources its claims cite were checked for support.
Mitochondrial DNA mutations and human disease
Open accessAbstract
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.
Overview
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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.
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Claims the paper makes
92 Not checked yet · 8 Own interpretation · 4 No basis given · 1 Partly supported · accuracy not yet measured
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In the paper
“Interestingly, m.3243A N G has been shown to impair methylation of mt-tRNA Leu(UUR) in cybrid osteosarcoma cells [196]”
§ Review Mitochondrial DNA mutations and human disease > 5.2.1. Molecular impacts of mt-tRNA mutations
What the sources say
- Partly supportedcites [196] Helm, 1999, Search for differences in post-transcriptional modification patterns of mitochondrial DNA-encoded wild-type and mutant human tRNALys and tRNALeu(UUR), Nucleic Acids Res. sourceExperimental — accuracy not yet measured
The ‘Modified nucleotide content of human mt tRNA Leu(UUR)’ section reports that cybrid cell line 43B carries A3243G and has about 50% less methylated G10 than the wild-type line. The ‘Cell lines and media’ section identifies 43B as a cybrid, but our copy does not identify it as an osteosarcoma cell line; that specific cell-type description is unverified. (LLM, conf=0.83)
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- Partly supported
None of the sources cited for this claim have been checked yet.
In the paper
“Although mtDNA repair systems do exist [51,52]”
§ Review Mitochondrial DNA mutations and human disease > 3. Clinical features of human mtDNA disease
What the sources say
plain- Asserted: passes — The authors put it forward as true.
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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
“The mitochondrial genome has a very high mutation rate, 10-to 17-fold higher than that observed in nuclear DNA.”
§ Review Mitochondrial DNA mutations and human disease > 3. Clinical features of human mtDNA disease
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“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].”
§ Review Mitochondrial DNA mutations and human disease > 3.2.2. MtDNA rearrangements
What the sources say
- Not checked yetcites [88][89][90]
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“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].”
§ Review Mitochondrial DNA mutations and human disease > 3.2.1. Point mutations
What the sources say
- Not checked yetcites [83] Sacconi, 2008, A functionally dominant mitochondrial DNA mutation, Hum. Mol. Genet. source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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].”
§ Review Mitochondrial DNA mutations and human disease > 3.1.4. MtDNA bottleneck
What the sources say
- Not checked yetcites [67][68][69][70][71][72]
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“For example, an average annual 1% decrease in m.3243A N G mutation levels in blood has been described [63].”
§ Review Mitochondrial DNA mutations and human disease > 3.1.2. Mitotic segregation
What the sources say
- Not checked yetcites [63] Rahman, 2001, Decrease of 3243 A–>G mtDNA mutation from blood in MELAS syndrome: a longitudinal study, Am. J. Hum. Genet. source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Over 80% of patients with MELAS have the m.3243A N G mutation in the MT-TL1 gene [109,110].”
§ Review Mitochondrial DNA mutations and human disease > 3.3.2.
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“In these children, there is a very high level of large-scale single mtDNA deletion present in all tissues [108].”
§ Review Mitochondrial DNA mutations and human disease > 3.3.1.4. Pearson syndrome.
What the sources say
- Not checked yetcites [108] Rotig, 1990, Pearson's marrow–pancreas syndrome. A multisystem mitochondrial disorder in infancy, J. Clin. Invest. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“There are three primary LHON mtDNA mutations (m.11778G N A, m.3460G N A, and m.14484T N C), which in total are present in at least 95% of LHON cases [56,124].”
§ Review Mitochondrial DNA mutations and human disease > 3.3.2.4. Leber's hereditary optic neuropathy (LHON).
What the sources say
- Not checked yetcites [56] MITOMAP: A Human Mitochondrial Genome Database. http://www.mitomap.org. 2009.
- Not checked yetcites [124] Man, 2002, Leber hereditary optic neuropathy, J. Med. Genet. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Probably not a substantial claim. 6
- It may state two separate claims as one. 36
In the paper
“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]”
§ Review Mitochondrial DNA mutations and human disease > Abstract
What the sources say
- Not checked yetcites [56] MITOMAP: A Human Mitochondrial Genome Database. http://www.mitomap.org. 2009.
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Also stated in: § 3. Clinical features of human mtDNA disease · plain
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
“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.”
§ Review Mitochondrial DNA mutations and human disease > 3.1. Specific features of mitochondrial disease
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
- 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.
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
“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.”
§ Review Mitochondrial DNA mutations and human disease > 3. Clinical features of human mtDNA disease
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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].”
§ Review Mitochondrial DNA mutations and human disease > 3.1.1. Threshold effect
What the sources say
- Not checked yetcites [62] Wong, 2007, Diagnostic challenges of mitochondrial DNA disorders, Mitochondrion source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- 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.
None of the sources cited for this claim have been checked yet.
In the paper
“Clonal expansion refers to the preferential amplification of mtDNA mutations to a high level in post-mitotic tissues [64,65].”
§ Review Mitochondrial DNA mutations and human disease > 3.1.3. Clonal expansion
What the sources say
- Not checked yetcites [64] Larsson, 1990, Progressive increase of the mutated mitochondrial DNA fraction in Kearns–Sayre syndrome, Pediatr. Res. source
- Not checked yetcites [65] Weber, 1997, A new mtDNA mutation showing accumulation with time and restriction to skeletal muscle, Am. J. Hum. Genet.
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably 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
“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]).”
§ Review Mitochondrial DNA mutations and human disease > 3.3.2.2. Chronic progressive external ophthalmoplegia (CPEO).
What the sources say
- Not checked yetcites [119] Moraes, 1989, Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns–Sayre syndrome, N. Engl. J. Med. source
- Not checked yetcites [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
- Not checked yetcites [121] Moraes, 1993, Atypical clinical presentations associated with the MELAS mutation at position 3243 of human mitochondrial DNA, Neuromuscul. Disord. source
- Not checked yetcites [122] Cardaioli, 2008, Chronic progressive external ophthalmoplegia: a new heteroplasmic tRNA(Leu(CUN)) mutation of mitochondrial DNA, J. Neurol. Sci. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Single mtDNA deletions occur sporadically early in development, and the identical deletion is present in all cells within affected tissues [87].”
§ Review Mitochondrial DNA mutations and human disease > 3.2.2. MtDNA rearrangements
What the sources say
- Not checked yetcites [87] Chen, 1995, Rearranged mitochondrial genomes are present in human oocytes, Am. J. Hum. Genet.
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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].”
§ Review Mitochondrial DNA mutations and human disease > 3.3.1. Mitochondrial diseases with onset in early infancy/childhood 3.3.1.1. Leigh syndrome.
What the sources say
- Not checked yetcites [105] Finsterer, 2008, Leigh and Leigh-like syndrome in children and adults, Pediatr. Neurol. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“They mainly occur between the origins of replication, O H and O L , and are typically flanked by short direct repeats [94,95].”
§ Review Mitochondrial DNA mutations and human disease > 3.2.2. MtDNA rearrangements
What the sources say
- Not checked yetcites [94] Bua, 2006, Mitochondrial DNA-deletion mutations accumulate intracellularly to detrimental levels in aged human skeletal muscle fibers, Am. J. Hum. Genet. source
- Not checked yetcites [95] Samuels, 2004, Two direct repeats cause most human mtDNA deletions, Trends Genet. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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].”
§ Review Mitochondrial DNA mutations and human disease > 3.2.2. MtDNA rearrangements
What the sources say
- Not checked yetcites [86] Schon, 1989, A direct repeat is a hotspot for large-scale deletion of human mitochondrial DNA, Science source
plain- Asserted: passes — The authors put it forward as true.
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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
“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.”
§ Review Mitochondrial DNA mutations and human disease > 5.1.3. Mouse models
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may be too vague to check against evidence.
None of the sources cited for this claim have been checked yet.
In the paper
“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].”
§ Review Mitochondrial DNA mutations and human disease > 5.1.1. Transmitochondrial cybrids
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“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].”
§ Review Mitochondrial DNA mutations and human disease > 4.1. Histochemical and biochemical testing
What the sources say
- Not checked yetcites [77] McFarland, 2002, Multiple neonatal deaths due to a homoplasmic mitochondrial DNA mutation, Nat. Genet. source
- Not checked yetcites [78] Taylor, 2003, A homoplasmic mitochondrial transfer ribonucleic acid mutation as a cause of maternally inherited hypertrophic cardiomyopathy, J. Am. Coll. Cardiol. source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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].”
§ Review Mitochondrial DNA mutations and human disease > 4.2. Molecular genetic testing
What the sources say
- Not checked yetcites [138] Whittaker, 2009, Urine heteroplasmy is the best predictor of clinical outcome in the m.3243A>G mtDNA mutation, Neurology source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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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
“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”
§ Review Mitochondrial DNA mutations and human disease > 5.1.1. Transmitochondrial cybrids
plaindirect- Asserted: passes — The authors put it forward as true.
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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
“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.”
§ Review Mitochondrial DNA mutations and human disease > 5. Functional characterisation of mtDNA mutations
hedged- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- 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.
In the paper
“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].”
§ Review Mitochondrial DNA mutations and human disease > 5.1.2. Yeast models
What the sources say
- Not checked yetcites [160] Bonnefoy, 2001, Genetic transformation of Saccharomyces cerevisiae mitochondria, Methods Cell Biol. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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].”
§ Review Mitochondrial DNA mutations and human disease > 5.1.2. Yeast models
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Review Mitochondrial DNA mutations and human disease > 5.1.3. Mouse models
What the sources say
- Not checked yetcites [172] Inoue, 2000, Generation of mice with mitochondrial dysfunction by introducing mouse mtDNA carrying a deletion into zygotes, Nat. Genet. source
- Not checked yetcites [173] Nakada, 2004, Accumulation of pathogenic DeltamtDNA induced deafness but not diabetic phenotypes in mito-mice, Biochem. Biophys. Res. Commun. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
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In the paper
“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].”
§ Review Mitochondrial DNA mutations and human disease > 5.1.2. Yeast models
What the sources say
- Not checked yetcites [163] De Luca, 2006, Mutations in yeast mt tRNAs: specific and general suppression by nuclear encoded tRNA interactors, Gene source
- Not checked yetcites [164] Montanari, 2008, Yeast as a model of human mitochondrial tRNA base substitutions: investigation of the molecular basis of respiratory defects, Rna source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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].”
§ Review Mitochondrial DNA mutations and human disease > 3.3.2.4. Leber's hereditary optic neuropathy (LHON).
What the sources say
- Not checked yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“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].”
§ Review Mitochondrial DNA mutations and human disease > 5.1.1. Transmitochondrial cybrids
What the sources say
- Not checked yetcites [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
plaindirectSingle case- Asserted: passes — The authors put it forward as true.
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In the paper
“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].”
§ Review Mitochondrial DNA mutations and human disease > 5.2. Molecular mechanisms of mitochondrial disease
What the sources say
- Not checked yetcites [187] Wong, 2002, Differentiation-specific effects of LHON mutations introduced into neuronal NT2 cells, Hum. Mol. Genet. source
- Not checked yetcites [188] Baracca, 2007, Biochemical phenotypes associated with the mitochondrial ATP6 gene mutations at nt8993, Biochim. Biophys. Acta source
- Not checked yetcites [175] Li, 2008, Increased ROS generation and SOD activity in heteroplasmic tissues of transmitochondrial mice with A3243G mitochondrial DNA mutation, Genet. Mol. Res. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Conversely, normal levels of ROS were measured in the POLG1 mutator mice, which eventually accumulate sufficient mtDNA mutations to cause severe OXPHOS deficiency [189].”
§ Review Mitochondrial DNA mutations and human disease > 5.2. Molecular mechanisms of mitochondrial disease
What the sources say
- Not checked yetcites [189] Trifunovic, 2005, Somatic mtDNA mutations cause aging phenotypes without affecting reactive oxygen species production, Proc. Natl. Acad. Sci. U. S. A. source
plaindirectSingle case- Asserted: passes — The authors put it forward as true.
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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
“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.”
§ Review Mitochondrial DNA mutations and human disease > 5.2. Molecular mechanisms of mitochondrial disease
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“and the mt-tRNA Tyr m.5874T N C and m.5877C N T transitions [204].”
§ Review Mitochondrial DNA mutations and human disease > 5.2.1. Molecular impacts of mt-tRNA mutations
What the sources say
- Not checked yetcites [204] Bonnefond, 2008, Decreased aminoacylation in pathology-related mutants of mitochondrial tRNATyr is associated with structural perturbations in tRNA architecture, RNA source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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].”
§ Review Mitochondrial DNA mutations and human disease > 5.2. Molecular mechanisms of mitochondrial disease
What the sources say
- Not checked yetcites [179] Wang, 1999, Dilated cardiomyopathy and atrioventricular conduction blocks induced by heart-specific inactivation of mitochondrial DNA gene expression, Nat. Genet. source
- Not checked yetcites [190] Wang, 2001, Increased in vivo apoptosis in cells lacking mitochondrial DNA gene expression, Proc. Natl. Acad. Sci. U. S. A. source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“However, although PNAs colocalised to mitochondria in intact cells, they were not able to cross the IMM.”
§ Review Mitochondrial DNA mutations and human disease > 6.2. Gene therapy
What the sources say
- Not checked yetcites [234] Taylor, 1997, Selective inhibition of mutant human mitochondrial DNA replication in vitro by peptide nucleic acids, Nat. Genet. source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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].”
§ Review Mitochondrial DNA mutations and human disease > 5.2.2. Global effects of mtDNA mutations
What the sources say
- Not checked yetcites [214] Jahangir Tafrechi, 2005, Distinct nuclear gene expression profiles in cells with mtDNA depletion and homoplasmic A3243G mutation, Mutat. Res. source
- Not checked yetcites [215] Alemi, 2007, Mitochondrial DNA deletions inhibit proteasomal activity and stimulate an autophagic transcript, Free Radic. Biol. Med. source
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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]”
§ Review Mitochondrial DNA mutations and human disease > 5.2.2. Global effects of mtDNA mutations
What the sources say
- Not checked yetcites [81] Temperley, 2003, Investigation of a pathogenic mtDNA microdeletion reveals a translation-dependent deadenylation decay pathway in human mitochondria, Hum. Mol. Genet. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Muscle conditioning enhanced ATP levels, delayed disease onset, and increased life expectancy in these mice.”
§ Review Mitochondrial DNA mutations and human disease > 6.1. Exercise therapy
What the sources say
- Not checked yetcites [231] Wenz, 2009, Endurance exercise is protective for mice with mitochondrial myopathy, J. Appl. Physiol. source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“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].”
§ Review Mitochondrial DNA mutations and human disease > 6.1. Exercise therapy
What the sources say
- Not checked yetcites [228] Taivassalo, 2005, Exercise and training in mitochondrial myopathies, Med. Sci. Sports Exerc. source
- Not checked yetcites [229] Jeppesen, 2006, Aerobic training is safe and improves exercise capacity in patients with mitochondrial myopathy, Brain source
- Not checked yetcites [230] Taivassalo, 2006, Endurance training and detraining in mitochondrial myopathies due to single large-scale mtDNA deletions, Brain source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Imported tRNA Lys molecules are correctly aminoacylated, able to participate in mitochondrial translation, and partially rescue mitochondrial functions [242].”
§ Review Mitochondrial DNA mutations and human disease > 6.2. Gene therapy
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The most recent mammalian mitochondrial compendium (MitoCarta) consists of 1098 identified proteins [209].”
§ Review Mitochondrial DNA mutations and human disease > 5.2.2. Global effects of mtDNA mutations
What the sources say
- Not checked yetcites [209] Pagliarini, 2008, A mitochondrial protein compendium elucidates complex I disease biology, Cell source
plain- Asserted: passes — The authors put it forward as true.
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Probably 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
“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.”
§ Review Mitochondrial DNA mutations and human disease > 6.2. Gene therapy
What the sources say
- Not checked yetcites [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 yetcites [166] Park, 2008, Overexpressed mitochondrial leucyl-tRNA synthetase suppresses the A3243G mutation in the mitochondrial tRNA(Leu(UUR)) gene, Rna source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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].”
§ Review Mitochondrial DNA mutations and human disease > 6.1. Exercise therapy
What the sources say
- Not checked yetcites [233] Murphy, 2008, Resistance training in patients with single, large-scale deletions of mitochondrial DNA, Brain source
boosteddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Indeed, AOX was well tolerated and transfectants displayed remarkable levels of cyanide resistance to mitochondrial metabolite oxidation.”
§ Review Mitochondrial DNA mutations and human disease > 6.2. Gene therapy
What the sources say
- Not checked yetcites [247] Hakkaart, 2006, Allotopic expression of a mitochondrial alternative oxidase confers cyanide resistance to human cell respiration, EMBO Rep. source
boosteddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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].”
§ Review Mitochondrial DNA mutations and human disease > 6.3. Prevention of mtDNA disease transmission
What the sources say
- Not checked yetcites [250] Dean, 2003, Prospect of preimplantation genetic diagnosis for heritable mitochondrial DNA diseases, Mol. Hum. Reprod. source
boosted- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Review Mitochondrial DNA mutations and human disease > 6.3. Prevention of mtDNA disease transmission
What the sources say
- Not checked yetcites Turnbull et al., unpublished data
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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].”
§ Review Mitochondrial DNA mutations and human disease > 6.3. Prevention of mtDNA disease transmission
What the sources say
- Not checked yetcites [252] Tachibana, 2009, Mitochondrial gene replacement in primate offspring and embryonic stem cells, Nature source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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].”
§ Review Mitochondrial DNA mutations and human disease > 6.2. Gene therapy
What the sources say
- Not checked yetcites [247] Hakkaart, 2006, Allotopic expression of a mitochondrial alternative oxidase confers cyanide resistance to human cell respiration, EMBO Rep. source
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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].”
§ Review Mitochondrial DNA mutations and human disease > 6.2. Gene therapy
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
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.”
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
“More recently, estimates have increased the mutation rate from 10- to 17-fold higher in mtDNA than nuclear genomic (nDNA) (Tuppen et al., 2010).”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Tuppen et al., 2010
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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Review Mitochondrial DNA mutations and human disease > 3.3.2.4. Leber's hereditary optic neuropathy (LHON).
“There are three primary LHON mtDNA mutations (m.11778G N A, m.3460G N A, and m.14484T N C)”
§ Review Mitochondrial DNA mutations and human disease > 3.3.2.4. Leber's hereditary optic neuropathy (LHON).
“Whilst the majority of patients with m.11778A N G who have symptoms develop LHON”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Review Mitochondrial DNA mutations and human disease > 7. Perspectives
“13 essential RC polypeptides: ND1-ND4 and ND4L, subunits of complex I (green), CYTB, a subunit of complex III (purple), COI-COIII, catalytic subunits of complex IV (yellow), and ATP6 and ATP8, subunits of complex V (blue).”
§ Review Mitochondrial DNA mutations and human disease > 5.1.3. Mouse models
“Two heteroplasmic point mutations introduced in MT-ND6 (m.13885insC) and MT-CO1 (m.6589T N C) resulted in myopathy and cardiomyopathy [174]”
Citations
Cites
1 retracted
Endurance exercise is protective for mice with mitochondrial myopathy
Wenz, T., Diaz, F., Hernandez, D., & Moraes, C. T. (2009) · Journal of Applied Physiology · doi:10.1152/japplphysiol.91571.2008 · Cited by 78 · cited 1×
“Recently, the bene fi ts of daily aerobic exercise have been further demonstrated in conditional COX10 knockoutmice,whichtypicallydevelopseveremyopathy at ∼ 2.5 – 3 months [231].”
BackgroundInfluentialRetractedSequence and organization of the human mitochondrial genome
Anderson, S., Bankier, A. T., Barrell, B. G., de Bruijn, M. H. L., Coulson, A. R., Drouin, J., Eperon, I. C., Nierlich, D. P., Roe, B. A., Sanger, F., et al. (1981) · Nature · doi:10.1038/290457a0 · Cited by 9,740
Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA
Andrews, R. M., Kubacka, I., Chinnery, P. F., Lightowlers, R. N., Turnbull, D. M., & Howell, N. (1999) · Nature Genetics · doi:10.1038/13779 · Cited by 3,337 · cited 1×
“heavy (H) strands), circular genome, the complete sequence of which was fully elucidated in 1981 [11] and further revised in 1999 [12].”
BackgroundSelf-citationPremature ageing in mice expressing defective mitochondrial DNA polymerase
Trifunovic, A., Wredenberg, A., Falkenberg, M., Spelbrink, J. N., Rovio, A. T., Bruder, C. E., Bohlooly-Y, M., Gidlöf, S., Oldfors, A., Wibom, R., et al. (2004) · Nature · doi:10.1038/nature02517 · Cited by 2,734 · cited 1×
“Alternative and more successful approaches to developing mouse models of mitochondrial disease involve manipulating the nuclear genes that regulate mtDNA maintenance and replication, such as TFAM [176 – 182], POLG ( ‘ Mutator ’ model) [183], and PEO1 (Twinkle; ‘ Deletor ’ model) [184].”
BackgroundtRNA punctuation model of RNA processing in human mitochondria
Ojala, D., Montoya, J., & Attardi, G. M. (1981) · Nature · doi:10.1038/290470a0 · Cited by 2,561 · cited 2×
“Mitochondrial translation is characterised by a number of distinct features including RNA-poor mitoribosomes [48], bicistronic transcripts [49], partial stop codons in some of the transcripts that are completed by polyadenylation [31,50], and deviation from the standard genetic code.”
BackgroundMitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy
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“The fi rst pathogenic mtDNA mutations were identi fi ed in 1988 [54,55].”
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BackgroundA Mitochondrial Protein Compendium Elucidates Complex I Disease Biology
Pagliarini, D. J., Calvo, S. E., Chang, B., Sheth, S. A., Vafai, S. B., Ong, S.-E., Walford, G. A., Sugiana, C., Boneh, A., Chen, W. K., et al. (2008) · Cell · doi:10.1016/j.cell.2008.06.016 · Cited by 1,994 · cited 3×
“understanding of the role of mitochondria in health and disease [209,225,226].”
BackgroundMethodInfluentialMitochondrial DNA mutations in human disease
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“The fi rst pathogenic mtDNA mutations were identi fi ed in 1988 [54,55].”
BackgroundMethod
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Cited by
Sorted by citations
The Role of Oxidative Stress in Parkinson's Disease
Dias, V., Junn, E., & Mouradian, M. M. (2013) · Journal of Parkinson’s Disease · doi:10.3233/jpd-130230 · Cited by 1,845
“In aged and PD afflicted brains, high levels of mitochondrial DNA (mtDNA) deletions are found in pigmented neurons of the substantia nigra [192] [193] [194] [195], and ROS-mediated damage can result in mutations in the mitochondrial genome [196] [197] [198].”
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Effects of ionizing radiation on mitochondria
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Hypoxia induces mitochondrial protein lactylation to limit oxidative phosphorylation
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LRPPRC is necessary for polyadenylation and coordination of translation of mitochondrial mRNAs
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“Reduced mtDNA expression is a well-recognized cause of human mitochondrial disease (Tuppen et al , 2010) and is heavily implicated in age-associated diseases and ageing (Larsson, 2010; Wallace, 2010).”
Metadata
- Authors
- Tuppen, H. A. L., Blakely, E. L., Turnbull, D. M., & Taylor, R. W.
- Affiliations
- Newcastle University (GB)
- Corresponding author
- Taylor, Robert W.
- 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)
- 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
- bronze
- doi.org
- 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
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