Mitochondrial disease

doi:10.1016/S0140-6736(06)68970-8

The Lancet

Volume 368, Issue 9529, 1–7 July 2006, Pages 70-82

https://doi.org/10.1016/S0140-6736(06)68970-8 Get rights and content

Summary

Defects of mitochondrial metabolism cause a wide range of human diseases that include examples from all medical subspecialties. This review updates the topic of mitochondrial diseases by reviewing the most important recent advances in this area. The factors influencing inheritance, maintenance and replication of mtDNA are reviewed and the genotype-phenotype of mtDNA disorders has been expanded, with new insights into epidemiology, pathogenesis and its role in ageing. Recently identified nuclear gene mutations of mitochondrial proteins include mutations of frataxin causing Friedreich's ataxia, PINK1, DJ1 causing Parkinson's disease and POLG causing infantile mtDNA depletion syndrome, ophthalmoplegia, parkinsonism, male subfertility and, in a transgenic mouse model, premature senescence. Mitochondrial defects in neurodegenerative diseases include Parkinson's, Alzheimer's and Huntington's disease. Improved understanding of mtDNA inheritance and mutation penetrance patterns, and novel techniques for mtDNA modification offer significant prospects for more accurate genetic counselling and effective future therapies.

Section snippets

Structure

Mitochondria are intracellular double membrane-bound structures. Although traditionally considered as small isolated organelles within the cell, it is more likely that mitochondria form a complex branching network. The density of mitochondria varies from one tissue to another, and is related to that tissue's dependence upon oxidative phosphorylation for energy provision. Thus, neurones, and cardiac and skeletal muscle cells have a high density of mitochondria, which to some extent explains

MtDNA mutations

Investigating the epidemiology of mtDNA genetics is complicated by the wide spectrum of clinical presentation, the diverse range of mutations and the high carrier rate, all of which will lead to underestimates of prevalence. A population-based study of the A3243G mutation in northern Finland estimated prevalence at 16·3 per 100 000.²⁶ The mutation was found in 14% of patients with hypertrophic cardiomyopathy, 13% of patients with ophthalmoplegia, 7·4% of maternally inherited deafness, and 6·9%

Nuclear gene mutations

Although 72 of the 85 subunits of the OXPHOS system are encoded by nuclear DNA, translated on cytoribosomes and transported to the mitochondrion, mutations of these genes have only rarely been described. To some extent, this could be an indication of the deleterious nature of such mutations, with affected fetuses perhaps being aborted early in development. Mutations that have been described generally manifest in the neonatal period or early infancy, although occasional late-onset patients have

Coenzyme Q₁₀ deficiency

Coenzyme Q₁₀ is a lipophilic component of the respiratory chain that transfers electrons from complexes I and II, and from fatty acids and branched chain aminoacids via flavin-linked dehydrogenases, to complex III (figure 2). The first report of human disease associated with coenzyme Q₁₀ deficiency was in a patient with encephalomyopathy and recurrent myoglobinuria with ragged red fibres and changes of lipid storage on muscle biopsy.⁷⁶ Severe coenzyme Q₁₀ deficiency was then described in six

Mitochondria and neurodegenerative diseases

Abnormalities of mtDNA or OXPHOS activity have been identified in several different neurodegenerative diseases. An important issue is whether these represent primary abnormalities or defects because of other factors not directly related to pathogenesis. To some extent, this could be a circular argument, at least in relation to whether improving mitochondrial function can improve the outcome of these diseases. If mitochondrial dysfunction contributes to pathogenesis, ameliorating its effects

Expansion of mitochondrial pathology

Mitochondria has long been thought to be involved in ageing. Two studies have highlighted the potential involvement of mitochondria in senescence.125, 126 The knock-in of a homozygous proof-reading deficient POLG genotype resulted in an accumulation of mtDNA point mutations and deletions and a phenotype that included shortened life-span, weight loss, osteoporosis, kyphosis, reduced subcutaneous fat, alopecia, reduced fertility, and cardiac hypertrophy.¹²⁵ These results support the proposition

Treatment of mitochondrial diseases

Treatment for diseases caused by mutations of mtDNA remains unsatisfactory and mostly confined to supportive measures, such as eye props or ptosis surgery for patients with CPEO. Although coenzyme Q₁₀ has shown some early promise in Parkinson's disease and Friedreich's ataxia, such results can only be regarded as provisional at this stage. There have been no large-scale studies to determine the effectiveness of coenzyme Q₁₀ in primary mtDNA diseases. Since defects of the respiratory chain

Conclusions

MtDNA mutations and mitochondrial dysfunction have been associated with, and implicated in, the aetiology and pathogenesis of a wide range of multi-system human diseases. The spectrum of mitochondrial diseases has been expanded by the recognition that mutations in the genes for nuclear-encoded mitochondrial proteins cause not only a number of neurodegenerative diseases but also haematological and ophthalmological disorders. Toxic influences of drugs such as the reverse transcriptase inhibitors

Search strategy and selection criteria

References for this review were identified by searches of PubMed and MEDLINE using the search terms “mitochondrial DNA”, “polymerase gamma” between 2000 and 2005. References were also identified from relevant articles and through searches of the author's files. Only papers reviewed in English were selected.

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Primary mitochondrial diseases (PMD) are amongst the most common inborn errors of metabolism causing fatal outcomes within the first decade of life. With marked heterogeneity in both inheritance patterns and physiological manifestations, these conditions present distinct challenges for targeted drug therapy, where effective therapeutic countermeasures remain elusive within the clinic. Hydrogen sulfide (H₂S)-based therapeutics may offer a new option for patient treatment, having been proposed as a conserved mitochondrial substrate and post-translational regulator across species, displaying therapeutic effects in age-related mitochondrial dysfunction and neurodegenerative models of mitochondrial disease. H₂S can stimulate mitochondrial respiration at sites downstream of common PMD-defective subunits, augmenting energy production, mitochondrial function and reducing cell death. Here, we highlight the primary signalling mechanisms of H₂S in mitochondria relevant for PMD and outline key cytoprotective proteins/pathways amenable to post-translational restoration via H₂S-mediated persulfidation. The mechanisms proposed here, combined with the advent of potent mitochondria-targeted sulfide delivery molecules, could provide a framework for H₂S as a countermeasure for PMD disease progression.
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The application of integrated systems biology to the field of structural biology is a promising new direction, although it is still in the infant stages of development. Here we report the use of single particle cryo-EM to identify multiple proteins from three enriched heterogeneous fractions prepared from human liver mitochondrial lysate. We simultaneously identify and solve high-resolution structures of nine essential mitochondrial enzymes with key metabolic functions, including fatty acid catabolism, reactive oxidative species clearance, and amino acid metabolism. Our methodology also identified multiple distinct members of the acyl-CoA dehydrogenase family. This work highlights the potential of cryo-EM to explore tissue proteomics at the atomic level.
Clinical and biochemical footprints of inherited metabolic diseases. XIII. Respiratory manifestations
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At any age, respiratory manifestations are a major cause of increased morbidity and mortality of inherited metabolic diseases (IMDs). Type and severity are extremely variable, this depending on the type of the underlying disorder. Symptoms and signs originating from upper or lower airways and/or thoracic wall and/or respiratory muscles involvement can occur either at presentation or in the late clinical course. Acute respiratory symptoms can trigger metabolic decompensation which, in turn, makes airway symptoms worse, creating a vicious circle. We have identified 181 IMDs associated with various types of respiratory symptoms which were classified into seven groups according to the type of clinical manifestations affecting the respiratory system: (i) respiratory failure, (ii) restrictive lung disease, (iii) interstitial lung disease, (iv) lower airway disease, (v) upper airway obstruction, (vi) apnea, and (vii) other. We also provided a list of investigations to be performed based on the respiratory phenotypes and indicated the therapeutic strategies currently available for IMD-associated airway disease. This represents the thirteenth issue in a series of educational summaries providing a comprehensive and updated list of metabolic differential diagnoses according to system involvement.
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Alzheimer's disease (AD) is known as an age-related irreversible neurodegenerative disease. AD seriously endangers the health of the elderly, but there is still no effective treatment. In the past several decades, the significant role of astrocytes in the process of AD has been universally acknowledged. In addition, extracellular vesicles (EVs) have been recognized as an essential mediator in intercellular communication and participate in various pathophysiological processes by carrying and transporting diverse cargoes. Moreover, specific conditions and stimuli can modulate the amount and properties of astrocyte-derived EVs (ADEVs) to affect AD progression. Thus, recent studies focused on the involvement of ADEVs in the pathogenesis of AD and the potential application of ADEVs in the diagnosis and treatment of AD, which provides a new direction and possibility for revealing the mystery of AD. Interestingly, it can be concluded that ADEVs have both pathogenic and protective effects in the process of AD through a comprehensive generalization. In this review, we aim to summarize the multi-faces of ADEVs effects on AD development, which can provide a novel strategy to investigate the underlying mechanism in AD. We also summarize the current ADEVs clinically relevant studies to raise the potential use of ADEVs in the discovery of novel biomarkers for diagnosis and therapeutic targets for AD.
Molecular characterization of variants in mitochondrial DNA encoded genes using next generation sequencing analysis and mitochondrial dysfunction in women with PCOS
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Emerging studies indicates mitochondrial dysfunction and involvement of mitochondrial DNA (mtDNA) variants in the pathogenesis of polycystic ovary syndrome (PCOS). Cumulative effect of mtDNA rare variants are now gaining considerable interest apart from common variants in the pathogenesis of complex diseases. Rare variants may modify the effect of polymorphism or in combination with the common variants may affect the risk of disease. With the evolution of high throughput sequencing techniques, which can be utilized to identify common as well as rare variants along with heteroplasmy levels, comprehensive characterization of the mtDNA variants is possible. Till date, few studies reported common mtDNA variants using traditional sequencing techniques but rare variants in mtDNA encoding genes remain unexplored in women with PCOS. These mtDNA variants may be responsible for mitochondrial dysfunction and may contribute in PCOS pathogenesis. In this study we determined mtDNA copy number, a biomarker of mitochondrial dysfunction and first time analysed variants in mtDNA encoded genes in women with PCOS using mitochondrial Next Generation sequencing (NGS) approach and compared allele frequency from mitochondrial 1000 genome dataset. Variant annotation and prioritization was done using highly automated pipeline, MToolBox that excludes reads mapped from nuclear mitochondrial DNA sequences (NumtS) to identify unique mtDNA reads. The present study identified significant reduction in mtDNA copy number in women with PCOS compared to non-PCOS women. A total of unique 214 prioritized common to rare variants were identified in mtDNA encoded genes, 183 variants in OXPHOS complexes, 14 variants in MT-tRNA and 17 variants in MT-rRNA genes that may be involved in mitochondrial dysfunction in PCOS. Numerous variants were heteroplasmic, pathogenic in nature and occurred in evolutionary conserved region. Heteroplasmic variants were more frequently occurred in MT-CO3 gene. Non-synonymous variants were more than synonymous variants and mainly occurred in OXPHOS complex I and IV. Few variants were found to be associated with diseases in MITOMAP database. The study provides a better understanding towards pathogenesis of PCOS from novel aspects focusing on mitochondrial genetic defects as underlying cause for contributing mitochondrial dysfunction in women with PCOS.
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ReviewMitochondrial disease

Summary

Section snippets

Structure

MtDNA mutations

Nuclear gene mutations

Coenzyme Q10 deficiency

Mitochondria and neurodegenerative diseases

Expansion of mitochondrial pathology

Treatment of mitochondrial diseases

Conclusions

Search strategy and selection criteria

Lancet

Lancet

Gene

Am J Hum Genet

Reprod Biomed Online

Lancet

Am J Hum Genet

Lancet

Am J Hum Genet

J Biol Chem

Lancet

Gene

Am J Hum Genet

Am J Hum Genet

Am J Hum Genet

Lancet

Am J Pathol

J Biol Chem

Neurosci Lett

Am J Hum Genet

Exp Gerontol

The “new” mitochondrial disorders

J Neurol Neurosurg Psychiatry

Mitochondrial respiratory-chain diseases

N Engl J Med

Mitochondria

J Neurol Neurosurg Psychiatry

Mitochondrial DNA depletion can be prevented by dGMP and dAMP supplementation in a resting culture of deoxyguanosine kinase-deficient fibroblasts

Hum Mol Genet

Discovery of a major D-loop replication origin reveals two modes of human mtDNA synthesis

Science

Haplotype and phylogenetic analyses suggest that one European-specific mtDNA background plays a role in the expression of Leber hereditary optic neuropathy by increasing the penetrance of the primary mutations 11778 and 14484

Am J Hum Genet

Behaviour of a population of partially duplicated mitochondrial DNA molecules in cell culture: segregation, maintenance and recombination dependent upon nuclear background

Hum Mol Genet

Maintenance of human rearranged mitochondrial DNAs in long-term cultured transmitochondrial cell lines

Mol Biol Cell

Heterologous mitochondrial DNA recombination in human cells

Hum Mol Genet

Mitochondrial DNA transmission of the mitochondrial defect in Parkinson's disease

Ann Neurol

Paternal inheritance of mitochondrial DNA

N Engl J Med

No evidence for paternal mtDNA transmission to offspring or extra-embryonic tissues after ICSI

Mol Hum Reprod

Is paternal mitochondrial DNA transferred to the offspring following intracytoplasmic sperm injection?

J Assist Reprod Genet

Ubiquitin tag for sperm mitochondria

Nature

Lack of paternal inheritance of muscle mitochondrial DNA in sporadic mitochondrial myopathies

Ann Neurol

Genotypes from patients indicate no paternal mitochondrial DNA contribution

Ann Neurol

MELAS and MERRF. The relationship between maternal mutation load and the frequency of clinically affected offspring

Brain

A new X linked recessive deafness syndrome with blindness, dystonia, fractures, and mental deficiency is linked to Xq22

J Med Genet

A novel intronic mutation in the DDP1 gene in a family with X-linked dystonia-deafness syndrome

Arch Neurol

The epidemiology of pathogenic mitochondrial DNA mutations

Ann Neurol

The incidence of mitochondrial encephalomyopathies in childhood: clinical features and morphological, biochemical, and DNA abnormalities

Ann Neurol

Minimum birth prevalence of mitochondrial respiratory chain disorders in children

Brain

Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies

Nature

Mitochondrial encephalomyopathies: gene mutation

Review
Mitochondrial disease

Coenzyme Q₁₀ deficiency