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Cited by 681Mitochondrial Function and PathologyMetabolism and Genetic DisordersGenomics and Rare Diseases

The DOI matches its Crossref record; 261 of the 272 references it cites were found in a registry or an index; none of the 127 sources its claims cite is checked for support yet.

Mitochondrial DNA mutations and human disease

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

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

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

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

Key findings

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

Methods

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

Limitations

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

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

Integrity signals

Registry

Crossref · 10.1016/j.bbabio.2009.09.005

Cites

261 of 261 references verified0 citation errors · 0 not checkable

Statistics

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Verification

Claims the paper makes

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

  • Probably not a substantial claim. 6
  • It may state two separate claims as one. 36
42 of 42

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

    MtDNA point mutations are usually maternally inherited.

    “MtDNA point mutations are usually maternally inherited.”

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

    Clinical phenotypes of mitochondrial disorders are extremely heterogeneous.

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

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

    Most cybrid models are generated using aneuploid tumour cells.

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

  • The authors state this as an assumption.

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

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

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

    mtDNA disorders typically occur in highly aerobic cells.

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

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

    Fermentative yeast such as S. cerevisiae lack complex I.

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

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

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

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

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

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

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

  • LHON mutation is given in opposite directions

    Minor

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

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

    Minor

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

2 of 2

Citations

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Research works printed but not linked: 2

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

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

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