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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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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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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
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesThe 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
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIn 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]
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIn 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
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIn 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]
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn 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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesNone 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
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIn 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
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesNone of the sources cited for this claim have been checked yet.
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
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIn the paper
“It has subsequently been recognised that patients with a mutant load greater than 95% m.8993T N G have an onset in childhood with maternally inherited Leigh syndrome (MILS) [123].”
§ Review Mitochondrial DNA mutations and human disease > 3.3.2.3. Neuropathy, ataxia, and retinitis pigmentosa (NARP).
What the sources say
- Not checked yetcites [123] Tatuch, 1992, Heteroplasmic mtDNA mutation (T----G) at 8993 can cause Leigh disease when the percentage of abnormal mtDNA is high, Am. J. Hum. Genet.
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
- 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.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- 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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably 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
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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
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
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
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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
Tests✓ Asserted: passes✗ Checkable: fails✓ Load-bearing: passes✓ Based: passesProbably 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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
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
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
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
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear? Based: unclearIt may state two separate claims as one.
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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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
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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
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None of the sources cited for this claim have been checked yet.
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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
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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
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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
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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
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
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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.
LHON mutation is given in opposite directions
MinorThe LHON section identifies the mutation at position 11778 as G to A, but later in the same paragraph calls it A to G.
“There are three primary LHON mtDNA mutations (m.11778G N A, m.3460G N A, and m.14484T N C)”
“Whilst the majority of patients with m.11778A N G who have symptoms develop LHON”
Figure 1's list of 13 polypeptides omits ND5 and ND6
MinorThe 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.
“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).”
“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
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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
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DNA replication and transcription in mammalian mitochondria.
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BackgroundReplication And Transcription Of Vertebrate Mitochondrial Dna
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BackgroundRole of Adenine Nucleotide Translocator 1 in mtDNA Maintenance
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BackgroundInfluentialMitochondrial DNA mutations in disease and aging
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Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons
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“TFAM [176–182], POLG (‘Mutator’ model) [183], and PEO1 (Twinkle; ‘Deletor’ model) [184].”
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BackgroundSomatic mtDNA mutations cause aging phenotypes without affecting reactive oxygen species production
Trifunovic, A., Hansson, A., Wredenberg, A., Rovio, A. T., Dufour, E., Khvorostov, I., Spelbrink, J. N., Wibom, R., Jacobs, H. T., & Larsson, N.-G. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0508886102 · Cited by 555
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BackgroundMITOMAP: a human mitochondrial genome database
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“14484TNC), which in total are present in at least 95% of LHON cases [56,124].”
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BackgroundCree, L. M., Samuels, D. C., Lopes, S. M. C. D. S., Rajasimha, H. K., Wonnapinij, P., Mann, J. R., Dahl, H. M., & Chinnery, P. F. (2008) · Nature Genetics · doi:10.1038/ng.2007.63 · Cited by 502 · cited 1×
“A prevalent hypothesis is that the bottleneck occurs during embryonic development, driven by a marked reduction in mtDNA copy number in the germ line [73,74].”
BackgroundTreatment for mitochondrial disorders
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“005 administration of various pharmacological and biochemical agents, including vitamins, cofactors, metabolites, and electron acceptors, to correct or bypass the underlying RC defect has met with limited success (reviewed in [227]).”
BackgroundSelf-citationPrevalence of mitochondrial DNA disease in adults
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A mouse model of mitochondrial disease reveals germline selection against severe mtDNA mutations
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BackgroundThe mitochondrial DNA genetic bottleneck results from replication of a subpopulation of genomes
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“Finally, a third alternate view on the genetic bottleneck has recently been proposed [76].”
BackgroundPearson's marrow–pancreas syndrome. A multisystem mitochondrial disorder in infancy
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“Theymainly occur between the origins of replication, OH and OL, and are typically flanked by short direct repeats [94,95].”
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“TFAM [176–182], POLG (‘Mutator’ model) [183], and PEO1 (Twinkle; ‘Deletor’ model) [184].”
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BackgroundCoupled Leading- and Lagging-Strand Synthesis of Mammalian Mitochondrial DNA
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BackgroundMethodMitochondrial DNA mutations in human disease
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Tissue-specific selection for different mtDNA genotypes in heteroplasmic mice
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BackgroundReconstitution of a minimal mtDNA replisome in vitro
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“Core components of the mitochondrial replisome include POLG, consisting of a catalytic subunit with 5 ′– 3 ′ exonuclease activity (PolgA) and a processivity subunit (PolgB), Twinkle, with 5 ′– 3 ′ DNA helicase activity, and mt-SSB [30].”
BackgroundBiochemical Assays of Respiratory Chain Complex Activity
Kirby, D. M., Thorburn, D. R., Turnbull, D. M., & Taylor, R. W. (2007) · Methods in cell biology · doi:10.1016/s0091-679x(06)80004-x · Cited by 383 · cited 1×
“…of individual RC enzyme complex activities in mitochondrial fractions or enriched homogenates prepared from fresh or frozen tissue samples [131]; some labs also investigate functional testing of intact organelles to include measurements of mitochondrial substrate oxidation, oxygen…”
BackgroundSelf-citationLeigh and Leigh-Like Syndrome in Children and Adults
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“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].”
BackgroundWhat causes mitochondrial DNA deletions in human cells?
Krishnan, K. J., Reeve, A. K., Samuels, D. C., Chinnery, P. F., Blackwood, J. K., Taylor, R. W., Wanrooij, S., Spelbrink, J. N., Lightowlers, R. N., & Turnbull, D. M. (2008) · Nature Genetics · doi:10.1038/ng.f.94 · Cited by 376
Self-citationDeletions of mitochondrial DNA in Kearns‐Sayre syndrome
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“The amount and tissue distribution of the deleted mtDNA are the most important factors in determining clinical symptoms, and not, as one might expect, the size and location of the deletions [99–101].”
BackgroundDistinct mitochondrial retrograde signals control the G1-S cell cycle checkpoint
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“However, increasing reports on the relationship of mitochondrial function to the cell cycle [22–24] suggest a connection between mtDNA replication and the cell cycle may well actually exist.”
BackgroundThe in-depth evaluation of suspected mitochondrial disease
Haas, R., Parikh, S., Falk, M. J., Saneto, R. P., Wolf, N. I., Darín, N., Wong, L.-J. C., Cohen, B. H., & Naviaux, R. K. (2008) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2007.11.018 · Cited by 363 · cited 1×
“Diagnostic algorithms and protocols are available for the molecular investigation of patients with suspected mtDNA disease [130,133,134].”
BackgroundThe mitochondrial bottleneck occurs without reduction of mtDNA content in female mouse germ cells
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“Paradoxically, it has also been suggested that the bottleneck occurs without reduction of germ line mtDNA copy number, but is a result of the preferential replication of a subgroup of mtDNAs during oogenesis [75].”
BackgroundLength-independent separation of DNA restriction fragments in two-dimensional gel electrophoresis
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“Denaturing gradient gel electrophoresis (DGGE) [139,140] and denaturing high-performance liquid chromatography (dHPLC) [141,142] have been available for some years, whilst emerging technologies include resequencing microarrays such as the Affymetrix MitoChip 2.0 [143,144].”
MethodInfluentialTyynismaa, H., Mjosund, K. P., Wanrooij, S., Lappalainen, I., Ylikallio, E., Jalanko, A., Spelbrink, J. N., Paetau, A., & Suomalainen, A. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0505551102 · Cited by 342 · 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].”
BackgroundRandom intracellular drift explains the clonal expansion of mitochondrial DNA mutations with age
Elson, J. L., Samuels, D. C., Turnbull, D. M., & Chinnery, P. F. (2001) · The American Journal of Human Genetics · doi:10.1086/318801 · Cited by 340 · cited 1×
“This expansion is thought to be a result of random genetic drift, dependent on relaxed replication of the mitochondrial genome [66].”
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“Other mutations in this mt-tRNA gene (e.g., m.3271T N C) [111], other mt-tRNA genes (e.g., m.1642G N A, MT-TV gene) [112] and protein-encoding genes (e.g., m.9957T N C in the MT-CO3 gene [113], several MT-ND5 mutations (m.12770A N G, m.13045A N C, m.13513G N A and m.13514A N G) [114 – 117] and…”
BackgroundProgressive Increase of the Mutated Mitochondrial DNA Fraction in Kearns-Sayre Syndrome
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“Clonal expansion refers to the preferential ampli fi cation of mtDNA mutations to a high level in post-mitotic tissues [64,65].”
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Metodiev, M. D., Lesko, N., Park, C. B., Cámara, Y., Shi, Y., Wibom, R., Hultenby, K. R., Gustafsson, C. M., & Larsson, N. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2009.03.001 · Cited by 310 · cited 1×
“…transcription machinery consists of a limited number of nuclear-encoded proteins: the dedicated mitochondrial RNA polymerase (POLRMT), the transcription activator TFAM, the transcription factor TFB2M (but probably not TFB1M as previously thought [33,34]), and the termination factor mTERF [35].”
BackgroundWang, Y., & Bogenhagen, D. F. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m604501200 · Cited by 303 · cited 1×
“Multiple copies (∼6–10) of mtDNA are organised in stable protein–DNAmacrocomplexes, termed nucleoids, which are primarily IMMassociated [14,15] andmay be exchanged betweenmitochondria.”
BackgroundIncreased mitochondrial mass in mitochondrial myopathy mice
Wredenberg, A., Wibom, R., Wilhelmsson, H., Graff, C., Wiener, H. H., Burden, S. J., Oldfors, A., Westerblad, H., & Larsson, N.-G. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.232591499 · Cited by 302 · cited 1×
“TFAM [176–182], POLG (‘Mutator’ model) [183], and PEO1 (Twinkle; ‘Deletor’ model) [184].”
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“Finally, decreased mt-tRNA stability has been described with the m.8344A N G mutation both in vitro and in cybrid osteosarcoma cells [198,202].”
BackgroundQuantitative Proteomic Comparison of Rat Mitochondria from Muscle, Heart, and Liver
Forner, F., Foster, L. J., Campanaro, S., Valle, G., & Mann, M. (2006) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m500298-mcp200 · Cited by 280 · cited 1×
“Mostly, current efforts are concentrating on elucidating the complete mammalian mitochondrial proteome, a critical step in furthering our understanding of the role of mitochondria in health and disease [209,225,226].”
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“The amount and tissue distribution of the deleted mtDNA are the most important factors in determining clinical symptoms, and not, as one might expect, the size and location of the deletions [99–101].”
BackgroundDiagnoses of neuronal ceroid‐lipofuscinosis by immunochemical methods
Hosain, S. A., Kaufmann, W. E., Negrin, G., Watkins, P. A., Siakotos, A. N., Palmer, D. N., & Naidu, S. (1995) · American Journal of Medical Genetics · doi:10.1002/ajmg.1320570226 · Cited by 256
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“TFAM also binds to other regions of the D-loop; however, only binding to the CSB region is shown. begins shortly after replication initiation and is the result of the generation of short Okazaki ribonucleotide fragments, subsequently converted to DNA [28].”
BackgroundNucleotide sequence evidence for rapid genotypic shifts in the bovine mitochondrial DNA D-loop
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“mtDNA bottleneck during development [67–72].”
Selective inhibition of mutant human mitochondrial DNA replication in vitro by peptide nucleic acids
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“Antigenomic therapy, which involves using sequence-specific nucleic acid derivatives that selectively target and inhibit the replication of mutated mtDNA thus allowing the wild-type genome to propagate, showed promising initial results in vitro with peptide nucleic acids (PNAs) [234].”
BackgroundHuman mitochondrial tRNAs in health and disease
Florentz, C., Sohm, B., Tóth, P., P�tz, J., & Sissler, M. (2003) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-003-2343-1 · Cited by 249 · cited 1×
“For more in-depth reviews of the effects of mutations on mt-tRNA structure and function see references [206 – 208].”
BackgroundMapping of mitochondrial DNA of individual sheep and goats: Rapid evolution in the D loop region
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BackgroundIncreased in vivo apoptosis in cells lacking mitochondrial DNA gene expression
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ResultInfluentialDecrease of 3243 A–>G mtDNA mutation from blood in MELAS syndrome: a longitudinal study
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“…common mt-tRNA Leu(UUR) m.3243A N G mutation, which interferes with a transcription termination site located at the boundary of the 16S mt-rRNA and mt-tRNA Leu(UUR) genes, causing accumulation of an unprocessed RNA intermediate (RNA19) including 16S mt-rRNA, mt-tRNA Leu(UUR) and MTND1 [191 – 193].”
BackgroundMitochondrial DNA polymerase-γ and human disease
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“, SLC25A4) [88–90].”
Taivassalo, T., Gardner, J. L., Taylor, R. W., Schaefer, A. M., Newman, J., Barron, M. J., Haller, R. G., & Turnbull, D. M. (2006) · Brain · doi:10.1093/brain/awl282 · Cited by 220 · cited 1×
“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 [228–230].”
BackgroundSelf-citationRescue of a mitochondrial deficiency causing Leber hereditary optic neuropathy
Guy, J., Qi, X., Pallotti, F., Schon, E. A., Manfredi, G., Carelli, V., Martinuzzi, A., Hauswirth, W. W., & Lewin, A. S. (2002) · Annals of Neurology · doi:10.1002/ana.10354 · Cited by 215 · cited 1×
“Initial attempts to recover respiratory defects in cybrids harbouring MT-ATP6 and MT-ND1 mutations, by engineered nuclear expression of their wild-type proteins [238,239], have been improved recently by forcing mRNA localisation to the mitochondrial surface, which ensures maximal mitochondrial translocation of the hig…”
BackgroundNovel DNA mismatch-repair activity involving YB-1 in human mitochondria
de Souza-Pinto, N. C., Mason, P. A., Hashiguchi, K., Weissman, L., Tian, J., Guay, D., Lebel, M., Stevnsner, T. V., Rasmussen, L. J., & Bohr, V. A. (2009) · DNA repair · doi:10.1016/j.dnarep.2009.01.021 · Cited by 214
Aerobic training is safe and improves exercise capacity in patients with mitochondrial myopathy
Jeppesen, T. D., Schwartz, M., Olsen, D. B., Wibrand, F., Krag, T., Duno, M., Hauerslev, S., & Vissing, J. (2006) · Brain · doi:10.1093/brain/awl149 · Cited by 211
Silvestri, G., Ciafaloni, E., Santorelli, F. M., Shanske, S., Servidei, S., Graf, W. D., Sumi, M., & DiMauro, S. (1993) · Neurology · doi:10.1212/wnl.43.6.1200 · Cited by 201
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“Considered evolutionary relics of ancient bacterial symbionts, mitochondria have gradually transferred the vast majority of their genetic material to the nucleus [10].”
BackgroundA new mtDNA mutation showing accumulation with time and restriction to skeletal muscle.
Weber, K., Wilson, J., Taylor, L., Brierley, E. J., Johnson, M. A., Turnbull, D. M., & Bindoff, L. A. (1997) · PubMed · Cited by 199
Self-citationEthidium Bromide-Induced Loss of Mitochondrial DNA from Primary Chicken Embryo Fibroblasts
Desjardins, P., Frost, E. H., & Morais, R. (1985) · Molecular and Cellular Biology · doi:10.1128/mcb.5.5.1163-1169.1985 · Cited by 197 · cited 1×
“Following pioneering work by Morais and colleagues between 1985 and 1988 establishing avian ρ cells [151,152], the first transmitochondrial cytoplasmic hybrid cells (cybrids) using human ρ cells were described in 1989 [153].”
MethodChomyn, A., Enriquez, J. A., Micol, V., Fernandez-Silva, P., & Attardi, G. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m908734199 · Cited by 197
Random genetic drift determines the level of mutant mtDNA in human primary oocytes
Brown, D. T., Samuels, D. C., Michael, E. M., Turnbull, D. M., & Chinnery, P. F. (2001) · The American Journal of Human Genetics · doi:10.1086/318190 · Cited by 196 · cited 1×
“The outcome of speci fi c pregnancies remains unpredictable due to the genetic bottleneck, which leads to considerable variation in the proportion of mutant mtDNA in different offspring [248].”
BackgroundMitochondrial Disease—Its Impact, Etiology, and Pathology
McFarland, R., Taylor, R. W., & Turnbull, D. M. (2007) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/s0070-2153(06)77005-3 · Cited by 192 · cited 1×
“Since then, over 250 pathogenic mtDNA mutations (point mutations and rearrangements) have been characterised [56], shown to cause a wide variety of diseases with a heterogeneity of phenotypes and a variable age of onset [57].”
BackgroundSelf-citationThe diagnosis of mitochondrial muscle disease
Taylor, R. W., Schaefer, A. M., Barron, M. J., McFarland, R., & Turnbull, D. M. (2004) · Neuromuscular Disorders · doi:10.1016/j.nmd.2003.12.004 · Cited by 192 · cited 2×
“…interactions between the nuclear and mitochondrial genome, the laboratory diagnosis of mtDNA disease often involves piecing together information from clinical, histochemical, and biochemical testing to inform molecular testing, allowing the development of rational diagnostic algorithms [129,130].”
BackgroundMethodSelf-citationMutations of the mitochondrial ND1 gene as a cause of MELAS
Kirby, D. M., McFarland, R., Ohtake, A., Dunning, C. J. R., Ryan, M. T., Wilson, C. J., Ketteridge, D., Turnbull, D. M., Thorburn, D. R., & Taylor, R. W. (2004) · Journal of Medical Genetics · doi:10.1136/jmg.2004.020537 · Cited by 185 · cited 1×
“13514ANG) [114–117] and MT-ND1 mutations [118]) may also cause MELAS.”
BackgroundSelf-citationTwo direct repeats cause most human mtDNA deletions
Samuels, D. C., Schon, E. A., & Chinnery, P. F. (2004) · Trends in Genetics · doi:10.1016/j.tig.2004.07.003 · Cited by 185 · cited 1×
“They mainly occur between the origins of replication, O H and O L , and are typically fl anked by short direct repeats [94,95].”
BackgroundGenetic modification of survival in tissue-specific knockout mice with mitochondrial cardiomyopathy
Li, H., Wang, J., Wilhelmsson, H., Hansson, A., Thorén, P., Duffy, J., Rustin, P., & Larsson, N.-G. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.7.3467 · Cited by 185 · cited 1×
“TFAM [176–182], POLG (‘Mutator’ model) [183], and PEO1 (Twinkle; ‘Deletor’ model) [184].”
van der Giezen, M., & Tovar, J. (2005) · EMBO Reports · doi:10.1038/sj.embor.7400440 · Cited by 180 · cited 1×
“Furthermore, these organelles are central to iron – sulphur cluster biogenesis, the only entirely conserved function of eukaryote mitochondria [6].”
BackgroundTaylor, R. W., Giordano, C., Davidson, M. M., d’Amati, G., Bain, H. H., Hayes, C. M., Leonard, H., Barron, M. J., Casali, C., Santorelli, F. M., et al. (2003) · Journal of the American College of Cardiology · doi:10.1016/s0735-1097(03)00300-0 · Cited by 179
Self-citationDifferentiation-specific effects of LHON mutations introduced into neuronal NT2 cells
Wong, A. (2002) · Human Molecular Genetics · doi:10.1093/hmg/11.4.431 · Cited by 179 · cited 1×
“11778GNA LHON mutations [187], in lymphocytes with m.”
BackgroundAssigning pathogenicity to mitochondrial tRNA mutations: when ‘definitely maybe’ is not good enough
McFarland, R., Elson, J. L., Taylor, R. W., et al. (2004) · Trends in Genetics · doi:10.1016/j.tig.2004.09.014 · Cited by 176 · cited 1×
“nicity for a novel mtDNA variant, originally proposed by DiMauro and Schon [146] and applied by others [147,148], should be considered”
BackgroundSelf-citationBase excision repair in nuclear and mitochondrial DNA
Dianov, G. L., Souza-Pinto, N., Nyaga, S. G., Thybo, T., Stevnsner, T., & Bohr, V. A. (2001) · Progress in nucleic acid research and molecular biology · doi:10.1016/s0079-6603(01)68107-8 · Cited by 174 · cited 1×
“Although mtDNA repair systems do exist [51,52], they are not suf fi cient 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.”
BackgroundSkewed Segregation of the mtDNA nt 8993 (TrG) Mutation in Human Oocytes
Blok, R. B., Gook, D. A., Thorburn, D. R., & Dahl, H. M. (1997) · The American Journal of Human Genetics · doi:10.1086/515453 · Cited by 174
Quantitative neuropathological changes in presymptomatic Huntington's disease
Gómez‐Tortosa, E., MacDonald, M. E., Friend, J. C., Taylor, S. A., Weiler, L., Cupples, L. A., Srinidhi, J., Gusella, J. F., Bird, E. D., Vonsattel, J., et al. (2001) · Annals of Neurology · doi:10.1002/1531-8249(200101)49:1 · Cited by 174
Prevalence of Mitochondrial 1555A→G Mutation in European Children
Bitner-Glindzicz, M. A. K., Pembrey, M. E., Duncan, A., Heron, J., Ring, S. M., Hall, A. J., & Rahman, S. (2009) · New England Journal of Medicine · doi:10.1056/nejmc0806396 · Cited by 172
Identification of a Novel Mutation in the mtDNA ND5 Gene Associated with MELAS
Santorelli, F. M., Tanji, K., Kulikova, R., Shanske, S., Vilarinho, L., Hays, A. P., & DiMauro, S. (1997) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1997.7167 · Cited by 171 · cited 1×
“13514ANG) [114–117] and MT-ND1 mutations [118]) may also cause MELAS.”
BackgroundGene therapy for progeny of mito-mice carrying pathogenic mtDNA by nuclear transplantation
Sato, A., Kono, T., Nakada, K., Ishikawa, K., Inoue, S.-I., Yonekawa, H., & Hayashi, J.-I. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506197102 · Cited by 171 · cited 1×
“Previous studies in heteroplasmic mice have suggested the feasibility of this approach [253].”
BackgroundTaylor, R. W. (2001) · Nucleic Acids Research · doi:10.1093/nar/29.15.e74 · Cited by 171 · cited 1×
“Many laboratories, however, continue to directly sequence the entire mitochondrial genome in affected tissues, using over-lapping primer sets to ensure complete coverage of the 16.6 kb genome [145].”
BackgroundInfluentialSelf-citationMultiple neonatal deaths due to a homoplasmic mitochondrial DNA mutation
McFarland, R., Clark, K. M., Morris, A. A. M., Taylor, R. W., Macphail, S., Lightowlers, R. N., & Turnbull, D. M. (2002) · Nature Genetics · doi:10.1038/ng819 · Cited by 170 · cited 2×
“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].”
BackgroundSelf-citationCoordinate Induction of Energy Gene Expression in Tissues of Mitochondrial Disease Patients
Heddi, A., Stepien, G., Benke, P. J., & Wallace, D. C. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.33.22968 · Cited by 169 · cited 1×
“This response has previously been reported in muscle with over 88% levels of the m.3243A N G mutation [217], but it is also thought to represent a sustained effect of the cybridisation process [158].”
BackgroundSörensen, L., Ekstrand, M., Silva, J., Lindqvist, E., Xu, B., Rustin, P., Olson, L., & Larsson, N.-G. (2001) · The Journal of Neuroscience · doi:10.1523/jneurosci.21-20-08082.2001 · Cited by 167 · cited 1×
“TFAM [176–182], POLG (‘Mutator’ model) [183], and PEO1 (Twinkle; ‘Deletor’ model) [184].”
Sequence-specific modification of mitochondrial DNA using a chimeric zinc finger methylase
Minczuk, M., Papworth, M. A., Kolasinska, P., Murphy, M. P., & Klug, A. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0609502103 · Cited by 166
The MTERF family proteins: Mitochondrial transcription regulators and beyond
Roberti, M., Polosa, P. L., Bruni, F., Manzari, C., Deceglie, S., Gadaleta, M. N., & Cantatore, P. (2009) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2009.01.013 · Cited by 166 · cited 1×
“…transcription machinery consists of a limited number of nuclear-encoded proteins: the dedicated mitochondrial RNA polymerase (POLRMT), the transcription activator TFAM, the transcription factor TFB2M (but probably not TFB1M as previously thought [33,34]), and the termination factor mTERF [35].”
BackgroundResistance training in patients with single, large-scale deletions of mitochondrial DNA
Murphy, J. L., Blakely, E. L., Schaefer, A. M., He, L., Wyrick, P. S., Haller, R. G., Taylor, R. W., Turnbull, D. M., & Taivassalo, T. (2008) · Brain · doi:10.1093/brain/awn252 · Cited by 164 · cited 1×
“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 fi bres [233].”
BackgroundSelf-citationLarsson, N., Tulinius, M., Holme, E., Oldfors, A., Andersen, O., Wahlström, J., & Aasly, J. O. (1992) · Europe PMC (PubMed Central) · Cited by 163
Gene shifting: a novel therapy for mitochondrial myopathy
Taivassalo, T. (1999) · Human Molecular Genetics · doi:10.1093/hmg/8.6.1047 · Cited by 160 · cited 1×
“plasmy levels sufficiently to recover muscular function (termed “gene shifting”) [232].”
BackgroundGenetic heterogeneity and mitochondrial DNA heteroplasmy in Leber's hereditary optic neuropathy.
Holt, I. J., Miller, D. H., & Harding, A. E. (1989) · Journal of Medical Genetics · doi:10.1136/jmg.26.12.739 · Cited by 159 · cited 1×
“mtDNA bottleneck during development [67–72].”
Kolesnikova, O. A., Entelis, N. S., Jacquin-Becker, C., Goltzene, F., Chrzanowska-Lightowlers, Z. M., Lightowlers, R. N., Martin, R. P., & Tarassov, I. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh267 · Cited by 157 · cited 1×
“Imported tRNA molecules are correctly aminoacylated, able to participate in mitochondrial translation, and partially rescue mitochondrial functions [242].”
BackgroundRubio, M. A. T., Rinehart, J. J., Krett, B., Duvezin-Caubet, S., Reichert, A. S., Söll, D., & Alfonzo, J. D. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0804283105 · Cited by 154 · cited 1×
“[243] have demonstrated the import of cytosolic tRNA and tRNA in rat and humanmitochondria in vivo, by a mechanism distinct from that of protein import.”
BackgroundA new mutation associated with MELAS is located in a mitochondrial DNA polypeptide-coding gene
Manfredi, G., Schon, E. A., Moraes, C. T., Bonilla, E., Berry, G. T., Sladky, J. T., & DiMauro, S. (1995) · Neuromuscular Disorders · doi:10.1016/0960-8966(94)00079-o · Cited by 153 · cited 1×
“…m.3271T N C) [111], other mt-tRNA genes (e.g., m.1642G N A, MT-TV gene) [112] and protein-encoding genes (e.g., m.9957T N C in the MT-CO3 gene [113], several MT-ND5 mutations (m.12770A N G, m.13045A N C, m.13513G N A and m.13514A N G) [114 – 117] and MT-ND1 mutations [118]) may also cause…”
BackgroundSasarman, F., Antonická, H., & Shoubridge, E. A. (2008) · Human Molecular Genetics · doi:10.1093/hmg/ddn265 · Cited by 153 · cited 1×
“Similar abilities for EFTu in human myoblasts harbouring the m.3243A N G mutation [165] and leucyl-tRNA synthetase in transmi-tochondrial WS277.”
BackgroundMitochondrial DNA Mutations in Disease, Aging, and Neurodegeneration
Reeve, A. K., Krishnan, K. J., & Turnbull, D. M. (2008) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1427.016 · Cited by 149
Self-citationMammalian mitochondrial nucleoids: Organizing an independently minded genome
Holt, I. J., He, J., Mao, C.-C., Boyd-Kirkup, J. D., Martinsson, P., Sembongi, H., Reyes, A., & Spelbrink, J. N. (2007) · Mitochondrion · doi:10.1016/j.mito.2007.06.004 · Cited by 149 · cited 2×
“Key proteins involved in mtDNA replication, maintenance, repair, and recombination, such asmitochondrial single-stranded binding protein (mt-SSB), mitochondrial polymerase γ (POLG), and mitochondrial transcription factor A (TFAM), are just some of the major constituent proteins associated with these structures [15–17].”
BackgroundSteffann, J., Frydman, N., Gigarel, N., Burlet, P., Ray, P. F., Fanchin, R., Feyereisen, E., Kerbrat, V, Tachdjian, G., Bonnefont, J.-P., et al. (2006) · Journal of Medical Genetics · doi:10.1136/jmg.2005.032326 · Cited by 145 · cited 1×
“Despite its promise, PGD has only been successfully completed in one case of mtDNA disease [251].”
BackgroundNuclear genetic control of mitochondrial DNA segregation
Battersby, B. J., Loredo-Osti, J. C., & Shoubridge, E. A. (2003) · Nature Genetics · doi:10.1038/ng1073 · Cited by 144 · cited 1×
“However, the repeated observation of directional selection for one mtDNA genotype in certain tissues [170], mediated by single tissue-speci fi c factors [171], suggests these mouse models will be particularly important in our quest to understanding the basis of tissue speci fi city and mtDNA somatic…”
BackgroundMcCulloch, V., & Shadel, G. S. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.16.5816-5824.2003 · Cited by 142
Hakkaart, G. A. J., Dassa, E. P., Jacobs, H. T., & Rustin, P. (2005) · EMBO Reports · doi:10.1038/sj.embor.7400601 · Cited by 139 · cited 1×
“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].”
BackgroundEthidium bromide-induced loss of mitochondrial DNA from primary chicken embryo fibroblasts.
Desjardins, P., Frost, E., & Morais, R. (1985) · Molecular and Cellular Biology · doi:10.1128/mcb.5.5.1163 · Cited by 139
Serero, A., Giglione, C., Sardini, A., Martinez‐Sanz, J., & Meinnel, T. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m309770200 · Cited by 138 · cited 1×
“mtRRF [45,46], and the methionine aminopeptidase MAP1D, which removes N-terminal methionines [47].”
BackgroundThe neurology of mitochondrial DNA disease
McFarland, R., Taylor, R. W., & Turnbull, D. M. (2002) · The Lancet Neurology · doi:10.1016/s1474-4422(02)00159-x · Cited by 134 · cited 1×
“…interactions between the nuclear and mitochondrial genome, the laboratory diagnosis of mtDNA disease often involves piecing together information from clinical, histochemical, and biochemical testing to inform molecular testing, allowing the development of rational diagnostic algorithms [129,130].”
MethodSelf-citationSoleimanpour‐Lichaei, H. R., Kühl, I., Gaisne, M., Passos, J. F., Wydro, M. M., Rorbach, J., Temperley, R., Bonnefoy, N., Tate, W. P., Lightowlers, R. N., et al. (2007) · Molecular Cell · doi:10.1016/j.molcel.2007.06.031 · Cited by 132 · cited 1×
“[43].”
Nature of Mitochondrial DNA Deletions in Substantia Nigra Neurons
Reeve, A. K., Krishnan, K. J., Elson, J. L., Morris, C. M., Bender, A., Lightowlers, R. N., & Turnbull, D. M. (2008) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2007.09.018 · Cited by 132 · cited 1×
“Their mechanism of generation is also thought to be identical, irrespective of the clinical phenotype [96], although the exact method by which deletions are formed is currently under debate.”
BackgroundSelf-citationDiscovery of a Major D-Loop Replication Origin Reveals Two Modes of Human mtDNA Synthesis
Fish, J. L., Raule, N., & Attardi, G. M. (2004) · Science · doi:10.1126/science.1102077 · Cited by 131 · cited 2×
“A second more conventional replication method has been suggested in which coupled leading-lagging strand DNA replication, also initiating at O H , is coordinated [26,27].”
BackgroundMethodBonnet, C., Augustin, S., Ellouze, S., Bénit, P., Bouaita, A., Rustin, P., Sahel, J.-A., & Corral-Debrinski, M. (2008) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2008.04.018 · Cited by 130
Treatment for mitochondrial disorders
Chinnery, P. F., Majamaa, K., Turnbull, D. M., & Thorburn, D. R. (2006) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd004426.pub2 · Cited by 129
Self-citationKoc, E. C., & Spremulli, L. L. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m202498200 · Cited by 128 · cited 1×
“IF3) [38,39], four mitochondrial elongation factors (EFG1, EFG2, EFTs, and EFTu) [40–42], and at least one termination release factor, mtRF1a”
BackgroundMitochondria in cybrids containing mtDNA from persons with mitochondriopathies
Swerdlow, R. H. (2007) · Journal of Neuroscience Research · doi:10.1002/jnr.21167 · Cited by 128 · cited 2×
“For further details on the history, development and use of cybrids for the study of mtDNA mutations see Khan et al. [155] and Swerdlow [156].”
BackgroundShanske, S., Pancrudo, J., Kaufmann, P., Engelstad, K., Jhung, S., Lu, J., Naini, A., DiMauro, S., & Vivo, D. C. D. (2004) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.30220 · Cited by 127 · cited 1×
“…the addition of a radio-or fl uorescent label in the fi nal PCR cycle to permit accurate quanti fi cation of mtDNA heteroplasmy; however, the m.3243A N G mutation is positively selected against in this tissue, prompting the investigation of other noninvasive tissue samples for diagnosis [136,137].”
BackgroundMunakata, K., Iwamoto, K., Bundo, M., & Kato, T. (2005) · Biological Psychiatry · doi:10.1016/j.biopsych.2004.11.041 · Cited by 127
Genetic, pathogenetic, and phenotypic implications of the mitochondrial A3243G tRNALeu(UUR) mutation
Finsterer, J. (2007) · Acta Neurologica Scandinavica · doi:10.1111/j.1600-0404.2007.00836.x · Cited by 125 · cited 1×
“For more in-depth reviews of the effects of mutations on mt-tRNA structure and function see references [206 – 208].”
BackgroundYasukawa, T., Suzuki, T., Ishii, N., Ueda, T., Ohta, S., & Watanabe, K. (2000) · FEBS Letters · doi:10.1016/s0014-5793(00)01145-5 · Cited by 124
Shanske, S., Çoku, J., Lu, J., et al. (2008) · PubMed · doi:10.1001/archneurol.2007.67 · Cited by 124 · cited 1×
“13514ANG) [114–117] and MT-ND1 mutations [118]) may also cause MELAS.”
BackgroundPrevalence of Mitochondrial 1555A→G Mutation in Adults of European Descent
Vandebona, H., Mitchell, P., Manwaring, N., Griffiths, K., Gopinath, B., Wang, J. J., & Sue, C. M. (2009) · New England Journal of Medicine · doi:10.1056/nejmc0806397 · Cited by 124
Sequence variation in mitochondrial complex I genes: mutation or polymorphism?
Mitchell, A., Elson, J. L., Howell, N., Taylor, R. W., & Turnbull, D. M. (2005) · Journal of Medical Genetics · doi:10.1136/jmg.2005.032474 · Cited by 124
Self-citationIs the mitochondrial complex I ND5 gene a hot‐spot for MELAS causing mutations?
Liolitsa, D., Rahman, S., Benton, S., et al. (2002) · Annals of Neurology · doi:10.1002/ana.10435 · Cited by 123 · cited 1×
“…m.3271T N C) [111], other mt-tRNA genes (e.g., m.1642G N A, MT-TV gene) [112] and protein-encoding genes (e.g., m.9957T N C in the MT-CO3 gene [113], several MT-ND5 mutations (m.12770A N G, m.13045A N C, m.13513G N A and m.13514A N G) [114 – 117] and MT-ND1 mutations [118]) may also cause MELAS.”
BackgroundPohjoismäki, J. L. O., Goffart, S., Tyynismaa, H., Willcox, S., Ide, T., Kang, D., Suomalainen, A., Karhunen, P. J., Griffith, J. D., Holt, I. J., et al. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.016600 · Cited by 122
Nuclear genes and mitochondrial translation: a new class of genetic disease
Jacobs, H. T., & TURNBULL, D. (2005) · Trends in Genetics · doi:10.1016/j.tig.2005.04.003 · Cited by 118 · cited 1×
“Reviews on nuclear gene defects in mitochondrial disorders are available [7 – 9].”
BackgroundSelf-citationProtection by the NDI1 gene against neurodegeneration in a rotenone rat model of Parkinson's disease
Marella, M., Seo, B. B., Nakamaru-Ogiso, E., Greenamyre, J. T., Matsuno-Yagi, A., & Yagi, T. (2008) · PLoS ONE · doi:10.1371/journal.pone.0001433 · Cited by 116 · cited 1×
“Mitochondrial targeting of the S.cerevisiae single subunit NADH oxidase, Ndi1, has been shown to rescue complex I de fi ciency in human cells [244] and also protect against neurodegeneration in rats fed with MPTP, a hallucinogen known to cause a form of Parkinson's disease (PD) [245].”
BackgroundBiochemical phenotypes associated with the mitochondrial ATP6 gene mutations at nt8993
Baracca, A., Sgarbi, G., Mattiazzi, M., Casalena, G., Pagnotta, E., Valentino, M. L., Moggio, M. G., Lenaz, G., Carelli, V., & Solaini, G. (2007) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2007.05.005 · Cited by 116 · cited 1×
“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].”
BackgroundA functionally dominant mitochondrial DNA mutation
Sacconi, S., Salviati, L., Nishigaki, Y., Walker, W. F., Hernandez-Rosa, E., Trevisson, E., Delplace, S., Desnuelle, C., Shanske, S., Hirano, M., et al. (2008) · Human Molecular Genetics · doi:10.1093/hmg/ddn073 · Cited by 113 · cited 1×
“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 b 25% in clinically affected tissues [83].”
BackgroundThe human mitochondrial ribosome recycling factor is essential for cell viability
Rorbach, J., Richter‐Dennerlein, R., Wessels, H. J. C. T., Wydro, M. M., Pękalski, M. Ł., Farhoud, M. H., Kühl, I., Gaisne, M., Bonnefoy, N., Smeitink, J. A. M., et al. (2008) · Nucleic Acids Research · doi:10.1093/nar/gkn576 · Cited by 112 · cited 1×
“mtRRF [45,46], and the methionine aminopeptidase MAP1D, which removes N-terminal methionines [47].”
BackgroundTemperley, R., Seneca, S., Tońska, K., Bartnik, E., Bindoff, L., Lightowlers, R., & Chrzanowska-Lightowlers, Z. (2003) · Human Molecular Genetics · doi:10.1093/hmg/ddg238 · Cited by 110 · cited 2×
“However, an increasing number of pathogenic homoplasmic mutations, often affecting just a single tissue and characterised by incomplete penetrance, are being recognised [77–82].”
BackgroundYoneda, M., Tanno, Y., Horai, S., Ozawa, T., Miyatake, T., & Tsuji, S. (1990) · PubMed · Cited by 107
Complex I deficiency is Associated with 3243G:C Mitochondrial DNA in Osteosarcoma Cell Cybrids
Dunbar, D. R., Moonie, P., Zeviani, M., & Holt, I. J. (1996) · Human Molecular Genetics · doi:10.1093/hmg/5.1.123 · Cited by 107
Exercise and training in mitochondrial myopathies
TAIVASSALO, T., & HALLER, R. G. (2005) · Medicine & Science in Sports & Exercise · doi:10.1249/01.mss.0000177446.97671.2a · Cited by 106 · cited 1×
“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 – 230].”
Backgroundvan den Bosch, B. J. C. (2000) · Nucleic Acids Research · doi:10.1093/nar/28.20.e89 · Cited by 106 · cited 1×
“Denaturing gradient gel electrophoresis (DGGE) [139,140] and denaturing high-performance liquid chromatography (dHPLC) [141,142] have been available for some years, whilst emerging technologies include resequencing microarrays such as the Affymetrix MitoChip 2.0 [143,144].”
MethodInfluentialDavies, S. M. K., Rackham, O., Shearwood, A.-M. J., Hamilton, K. L., Narsai, R., Whelan, J., & Filipovska, A. (2009) · FEBS Letters · doi:10.1016/j.febslet.2009.04.048 · Cited by 105 · cited 1×
“Other recently identi fi ed nuclear-encoded factors are the translation regulator PTCD3 [44], the ribosome recycling factor mtRRF [45,46], and the methionine aminopeptidase MAP1D, which removes N-terminal methionines [47].”
BackgroundMouse models of mitochondrial DNA defects and their relevance for human disease
Tyynismaa, H., & Suomalainen, A. (2009) · EMBO Reports · doi:10.1038/embor.2008.242 · Cited by 105 · cited 1×
“However, these models are beyond the scope of the current review; for further details see Vempati et al. [185] and Tyynismaa and Suomalainen [186].”
MethodThe comeback of mitochondria to calcium signalling
Pozzan, T., Magalhães, P. M. R., & Rizzuto, R. (2000) · Cell Calcium · doi:10.1054/ceca.2000.0166 · Cited by 104 · cited 1×
“In addition to OXPHOS metabolism, mitochondria control cytosolic calcium concentration [2] and regulate apoptotic cell death [3].”
BackgroundImpact of disease-related mitochondrial mutations on tRNA structure and function
Wittenhagen, L. M. (2003) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2003.09.006 · Cited by 102 · cited 1×
“Formore in-depth reviews of the effects of mutations onmt-tRNA structure and function see references [206–208].”
BackgroundA tRNA suppressor mutation in human mitochondria
Meziane, A. E., Lehtinen, S. K., Hance, N., Nijtmans, L. G. J., Dunbar, D. R., Holt, I. J., & Jacobs, H. T. (1998) · Nature Genetics · doi:10.1038/ng0498-350 · Cited by 101 · cited 1×
“In addition, these cell models have challenged our established criteria for pathogenicity with the identi fi cation of the fi rst mt-tRNA suppressor mutation, m.12300G N A in MT-L2 [154], and the fi rst functionally dominant mt-tRNA mutation, m.5545C N T in MT-TW [155].”
BackgroundProtein import into mitochondria
Neupert, W., & Mokranjac, D. (2005) · Biochemical Society Transactions · doi:10.1042/bst20051019 · Cited by 100
Gaucher, S. P., Taylor, S. W., Fahy, E., Zhang, B., Warnock, D. E., Ghosh, S. S., & Gibson, B. W. (2004) · Journal of Proteome Research · doi:10.1021/pr034102a · Cited by 99 · cited 1×
“Mostly, current efforts are concentrating on elucidating the complete mammalian mitochondrial proteome, a critical step in furthering our understanding of the role of mitochondria in health and disease [209,225,226].”
BackgroundHelm, M., Florentz, C., Chomyn, A., & Attardi, G. (1999) · Nucleic Acids Research · doi:10.1093/nar/27.3.756 · Cited by 99
Bonnet, C., Kaltimbacher, V., Ellouze, S., Augustin, S., Bénit, P., Forster, V., Rustin, P., Sahel, J.-A., & Corral-Debrinski, M. (2007) · Rejuvenation Research · doi:10.1089/rej.2006.0526 · Cited by 98 · cited 1×
“Initial attempts to recover respiratory defects in cybrids harbouring MT-ATP6 and MT-ND1 mutations, by engineered nuclear expression of their wild-type proteins [238,239], have been improved recently by forcing mRNA localisation to the mitochondrial surface, which ensures maximal mitochondrial translocation of the hig…”
BackgroundURINE HETEROPLASMY IS THE BEST PREDICTOR OF CLINICAL OUTCOME IN THE m.3243A>G mtDNA MUTATION
Whittaker, R. G., Blackwood, J. K., Alston, C. L., Blakely, E. L., Elson, J. L., McFarland, R., Chinnery, P. F., Turnbull, D. M., & Taylor, R. W. (2009) · Neurology · doi:10.1212/01.wnl.0000342121.91336.4d · Cited by 98
Self-citationNoninvasive diagnosis of the 3243A>G mitochondrial DNA mutation using urinary epithelial cells
McDonnell, M. T., Schaefer, A. M., Blakely, E. L., McFarland, R., Chinnery, P. F., Turnbull, D. M., & Taylor, R. W. (2004) · European Journal of Human Genetics · doi:10.1038/sj.ejhg.5201216 · Cited by 96
Self-citationBacman, S. R., Williams, S. L., Hernandez, D., & Moraes, C. T. (2007) · Gene Therapy · doi:10.1038/sj.gt.3302981 · Cited by 93 · cited 1×
“…with both rat and mouse mtDNA and in a mouse model heteroplasmic for the BALB and NZB mtDNA haplotypes, this approach is limited to mtDNA mutations that introduce an additional restriction site although recent data demonstrate this restriction site need not be unique to the pathogenic genome [236].”
BackgroundDimerization of a pathogenic human mitochondrial tRNA
Wittenhagen, L. M., & Kelley, S. O. (2002) · Nature Structural Biology · doi:10.1038/nsb820 · Cited by 92 · cited 1×
“…G, in the DHU stem, is responsible for a dramatic structural change, which disrupts both the L-shaped tertiary fold of mt-tRNA Leu(UUR) by preventing np A14/U8 interaction [200] and its quaternary structure by promoting the formation of a dimeric complex by intermolecular D-loop base pairing [201].”
BackgroundGenetic transformation of Saccharomyces cerevisiae mitochondria
Bonnefoy, N., & Fox, T. D. (2001) · Methods in cell biology · doi:10.1016/s0091-679x(01)65022-2 · Cited by 89 · cited 1×
“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].”
BackgroundValidation of microarray-based resequencing of 93 worldwide mitochondrial genomes
Hartmann, A., Thieme, M., Nanduri, L. K., Stempfl, T., Moehle, C., Kivisild, T., & Oefner, P. J. (2008) · Human Mutation · doi:10.1002/humu.20816 · Cited by 87 · cited 1×
“Denaturing gradient gel electrophoresis (DGGE) [139,140] and denaturing high-performance liquid chromatography (dHPLC) [141,142] have been available for some years, whilst emerging technologies include resequencing microarrays such as the Affymetrix MitoChip 2.0 [143,144].”
MethodInfluentialRorbach, J., Yusoff, A. A. M., Tuppen, H. A. L., Kamaludin, D. P. A., Chrzanowska‐Lightowlers, Z. M., Taylor, R. W., Turnbull, D. M., McFarland, R., & Lightowlers, R. N. (2008) · Nucleic Acids Research · doi:10.1093/nar/gkn147 · Cited by 82 · cited 2×
“1624CNT 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 inmttRNA steady-state levels [159].”
BackgroundSelf-citationDiagnostic challenges of mitochondrial DNA disorders
Wong, L. C. (2006) · Mitochondrion · doi:10.1016/j.mito.2006.11.025 · Cited by 82 · cited 1×
“severity and the proportion of mtDNA mutation is lacking [62].”
BackgroundMitochondrial medicine: entering the era of treatment
Koene, S., & Smeitink, J. A. M. (2009) · Journal of Internal Medicine · doi:10.1111/j.1365-2796.2008.02058.x · Cited by 82 · cited 1×
“For comprehensive reviews regarding the treatment of mitochondrial disease, see references [235,254,255].”
BackgroundWoriax, V. L., Burkhart, W., & Spremulli, L. L. (1995) · Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression · doi:10.1016/0167-4781(95)00176-x · Cited by 80
Progress and prospects: gene therapy for mitochondrial DNA disease
Kyriakouli, D. S., Boesch, P., Taylor, R. W., & Lightowlers, R. N. (2008) · Gene Therapy · doi:10.1038/gt.2008.91 · Cited by 76 · cited 2×
“For comprehensive reviews regarding the treatment of mitochondrial disease, see references [235,254,255].”
BackgroundSelf-citationHomoplasmy, heteroplasmy, and mitochondrial dystonia
McFarland, R., Chinnery, P. F., Blakely, E. L., et al. (2007) · Neurology · doi:10.1212/01.wnl.0000267843.10977.4a · Cited by 76 · cited 1×
“Whilst the majority of patients with m.11778A N G who have symptoms develop LHON, there have been a few reports of other neurodegenerative phenotypes including early-onset dystonia [80].”
BackgroundSelf-citationAn Oligonucleotide Microarray for High-Throughput Sequencing of the Mitochondrial Genome
Zhou, S., Kassauei, K., Cutler, D. J., Kennedy, G. C., Sidransky, D., Maitra, A., & Califano, J. A. (2006) · Journal of Molecular Diagnostics · doi:10.2353/jmoldx.2006.060008 · Cited by 74 · cited 1×
“Denaturing gradient gel electrophoresis (DGGE) [139,140] and denaturing high-performance liquid chromatography (dHPLC) [141,142] have been available for some years, whilst emerging technologies include resequencing microarrays such as the Affymetrix MitoChip 2.0 [143,144].”
MethodInfluentialProspect of preimplantation genetic diagnosis for heritable mitochondrial DNA diseases
Dean, N. L. (2003) · Molecular Human Reproduction · doi:10.1093/molehr/gag077 · Cited by 74 · cited 1×
“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].”
BackgroundSeibel, P., Degoul, F., Bonne, G., Romero, N. B., François, D., Paturneau-Jouas, M., Ziegler, F., Eymard, B., Fardeau, M., Marsac, C., et al. (1991) · Journal of the Neurological Sciences · doi:10.1016/0022-510x(91)90148-z · Cited by 73
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“mtRRF [45,46], and the methionine aminopeptidase MAP1D, which removes N-terminal methionines [47].”
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Flagged first, then by citations
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Research works printed but not linked: 2
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Cited by
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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
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LRPPRC is necessary for polyadenylation and coordination of translation of mitochondrial mRNAs
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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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