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PloS One 2022Mitochondrial disease prevalence has been estimated at 1 in 4000 in the United States, and 1 in 5000 worldwide. Prevalence in Canada has not been established, though...
BACKGROUND
Mitochondrial disease prevalence has been estimated at 1 in 4000 in the United States, and 1 in 5000 worldwide. Prevalence in Canada has not been established, though multi-linked health administrative data resources present a unique opportunity to establish robust population-based estimates in a single-payer health system. This study used administrative data for the Ontario, Canada population between April 1988 and March 2019 to measure mitochondrial disease prevalence and describe patient characteristics and health care costs.
RESULTS
3069 unique individuals were hospitalized with mitochondrial disease in Ontario and eligible for the study cohort, representing a period prevalence of 2.51 per 10,000 or 1 in 3989. First hospitalization was most common between ages 0-9 or 50-69. The mitochondrial disease population experiences a high need for health care and incurred high costs (mean = CAD$24,023 in 12 months before first hospitalization) within the single-payer Ontario health care system.
CONCLUSIONS
This study provides needed insight into mitochondrial disease in Canada, and demonstrates the high health burden on patients. The methodology used can be adapted across jurisdictions with similar routine collection of health data, such as in other Canadian provinces. Future work should seek to validate this approach via record linkage of existing disease cohorts in Ontario, and identify specific comorbidities with mitochondrial disease that may contribute to high health resource utilization.
Topics: Canada; Child; Child, Preschool; Cohort Studies; Health Care Costs; Humans; Infant; Infant, Newborn; Mitochondrial Diseases; Ontario; Prevalence
PubMed: 35395012
DOI: 10.1371/journal.pone.0265744 -
Biomolecules Feb 2023The fruit fly-i.e., -has proven to be a very useful model for the understanding of basic physiological processes, such as development or ageing. The availability of... (Review)
Review
The fruit fly-i.e., -has proven to be a very useful model for the understanding of basic physiological processes, such as development or ageing. The availability of straightforward genetic tools that can be used to produce engineered individuals makes this model extremely interesting for the understanding of the mechanisms underlying genetic diseases in physiological models. Mitochondrial diseases are a group of yet-incurable genetic disorders characterized by the malfunction of the oxidative phosphorylation system (OXPHOS), which is the highly conserved energy transformation system present in mitochondria. The generation of models of mitochondrial disease started relatively recently but has already provided relevant information about the molecular mechanisms and pathological consequences of mitochondrial dysfunction. Here, we provide an overview of such models and highlight the relevance of as a model to study mitochondrial disorders.
Topics: Animals; Drosophila melanogaster; Drosophila; Mitochondria; Mitochondrial Diseases; Oxidative Phosphorylation
PubMed: 36830747
DOI: 10.3390/biom13020378 -
Journal of Child Neurology Sep 2014Mitochondrial DNA is replicated by DNA polymerase γ in concert with accessory proteins such as the mitochondrial DNA helicase, single-stranded DNA binding protein,... (Review)
Review
Mitochondrial DNA is replicated by DNA polymerase γ in concert with accessory proteins such as the mitochondrial DNA helicase, single-stranded DNA binding protein, topoisomerase, and initiating factors. Defects in mitochondrial DNA replication or nucleotide metabolism can cause mitochondrial genetic diseases due to mitochondrial DNA deletions, point mutations, or depletion, which ultimately cause loss of oxidative phosphorylation. These genetic diseases include mitochondrial DNA depletion syndromes such as Alpers or early infantile hepatocerebral syndromes, and mitochondrial DNA deletion disorders, such as progressive external ophthalmoplegia, ataxia-neuropathy, or mitochondrial neurogastrointestinal encephalomyopathy. This review focuses on our current knowledge of genetic defects of mitochondrial DNA replication (POLG, POLG2, C10orf2, and MGME1) that cause instability of mitochondrial DNA and mitochondrial disease.
Topics: Animals; DNA Replication; DNA, Mitochondrial; Humans; Mitochondria; Mitochondrial Diseases
PubMed: 24985751
DOI: 10.1177/0883073814537380 -
Mitochondrion 2007Recent progress in genetics and molecular biology has provided useful information regarding the molecular mechanisms associated with the mitochondrial diseases. Genetic... (Review)
Review
Recent progress in genetics and molecular biology has provided useful information regarding the molecular mechanisms associated with the mitochondrial diseases. Genetic approaches were initiated in the late 1980s to clarify the gene responsible for various mitochondrial diseases, and information concerning genetic mutations is currently used in the diagnosis of mitochondrial diseases. Moreover, it was also revealed that mitochondria play a central role in apoptosis, or programmed cell death, which is closely related to the loss of physiological functions of tissues. Therefore, drug therapies targeted to the mitochondria would be highly desirable. In spite of the huge amount of mechanism-based studies of mitochondrial diseases, effective therapies have not yet been established mainly because of the lack of an adequate delivery system. To date, numerous investigators have attempted to establish a mitochondrial drug delivery system. However, many problems remain to be overcome before a clinical application can be achieved. To fulfill a drug delivery targeted to mitochondria, we first need to establish a method to encapsulate various drugs, proteins, peptides, and genes into a drug carrier depending on their physical characteristics. Second, we need to target it to a specific cell. Finally, multi-processes of intracellular trafficking should be sophisticatedly regulated so as to release a drug carrier from the endosome to the cytosol, and thereafter to deliver to the mitochondria. In this review, we describe the current state of the development of mitochondrial drug delivery systems, and discuss the advantage and disadvantage of each system. Our current efforts to develop an efficient method for the packaging of macromolecules and regulating intracellular trafficking are also summarized. Furthermore, novel concept of "Regulation of intramitochondrial trafficking" is proposed herein as a future challenge to the development of a mitochondrial drug delivery system.
Topics: Animals; DNA, Mitochondrial; Drug Carriers; Gene Products, tat; Genetic Therapy; Humans; Liposomes; Mitochondria; Mitochondrial Diseases; Molecular Chaperones; Oligodeoxyribonucleotides; Peptide Nucleic Acids; Protein Transport; Rats
PubMed: 17296332
DOI: 10.1016/j.mito.2006.12.003 -
Scientific Reports Dec 2021Mitochondrial diseases are a group of heterogeneous genetic metabolic diseases caused by mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) gene mutations. Mining the...
Mitochondrial diseases are a group of heterogeneous genetic metabolic diseases caused by mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) gene mutations. Mining the gene-disease association of mitochondrial diseases is helpful for understanding the pathogenesis of mitochondrial diseases, for carrying out early clinical diagnosis for related diseases, and for formulating better treatment strategies for mitochondrial diseases. This project researched the relationship between genes and mitochondrial diseases, combined the Malacards, Genecards, and MITOMAP disease databases to mine the knowledge on mitochondrial diseases and genes, used database integration and the sequencing method of the phenolyzer tool to integrate disease-related genes from different databases, and sorted the disease-related candidate genes. Finally, we screened 531 mitochondrial related diseases, extracted 26,723 genes directly or indirectly related to mitochondria, collected 24,602 variant sites on 1474 genes, and established a mitochondrial disease knowledge base (MitDisease) with a core of genes, diseases, and variants. This knowledge base is helpful for clinicians who want to combine the results of gene testing for diagnosis, to understand the occurrence and development of mitochondrial diseases, and to develop corresponding treatment methods.
Topics: Data Mining; Databases, Genetic; Genetic Loci; Genetic Predisposition to Disease; Humans; Knowledge Bases; Mitochondrial Diseases; Phenotype; Polymorphism, Single Nucleotide
PubMed: 34903783
DOI: 10.1038/s41598-021-03249-0 -
Journal of Inherited Metabolic Disease Jul 2015Mitochondrial respiratory chain deficiencies exhibit a wide spectrum of clinical presentations owing to defective mitochondrial energy production through oxidative... (Review)
Review
Mitochondrial respiratory chain deficiencies exhibit a wide spectrum of clinical presentations owing to defective mitochondrial energy production through oxidative phosphorylation. These defects can be caused by either mutations in the mitochondrial DNA (mtDNA) or mutations in nuclear genes coding for mitochondrially-targeted proteins. The underlying pathomechanisms can affect numerous pathways involved in mitochondrial biology including expression of mtDNA-encoded genes. Expression of the mitochondrial genes is extensively regulated at the post-transcriptional stage and entails nucleolytic cleavage of precursor RNAs, RNA nucleotide modifications, RNA polyadenylation, RNA quality and stability control. These processes ensure proper mitochondrial RNA (mtRNA) function, and are regulated by dedicated, nuclear-encoded enzymes. Recent growing evidence suggests that mutations in these nuclear genes, leading to incorrect maturation of RNAs, are a cause of human mitochondrial disease. Additionally, mutations in mtDNA-encoded genes may also affect RNA maturation and are frequently associated with human disease. We review the current knowledge on a subset of nuclear-encoded genes coding for proteins involved in mitochondrial RNA maturation, for which genetic variants impacting upon mitochondrial pathophysiology have been reported. Also, primary pathological mtDNA mutations with recognised effects upon RNA processing are described.
Topics: DNA, Mitochondrial; Humans; Mitochondria; Mitochondrial Diseases; RNA
PubMed: 26016801
DOI: 10.1007/s10545-015-9859-z -
Brain : a Journal of Neurology Oct 2017Mitochondrial disorders are genetically determined metabolic diseases due to a biochemical deficiency of the respiratory chain. Given that multi-system involvement and... (Review)
Review
Mitochondrial disorders are genetically determined metabolic diseases due to a biochemical deficiency of the respiratory chain. Given that multi-system involvement and disease progression are common features of mitochondrial disorders they carry substantial morbidity and mortality. Despite this, no disease-modifying treatments exist with clear clinical benefits, and the current best management of mitochondrial disease is supportive. Several therapeutic strategies for mitochondrial disorders are now at a mature preclinical stage. Some are making the transition into early-phase patient trials, but the lack of validated biomarkers of disease progression presents a challenge when developing new therapies for patients. This update discusses current biomarkers of mitochondrial disease progression including metabolomics, circulating serum markers, exercise physiology, and both structural and functional imaging. We discuss the advantages and disadvantages of each approach, and consider emerging techniques with a potential role in trials of new therapies.
Topics: Biomarkers; Cytokines; Disease Progression; Humans; Metabolomics; Mitochondrial Diseases; Neuroimaging
PubMed: 28969370
DOI: 10.1093/brain/awx168 -
Current Opinion in Ophthalmology Sep 2011Mitochondrial disease is a heterogeneous group of energy metabolism disorders that present across all ages with a wide range of ocular or multisystemic manifestations.... (Review)
Review
PURPOSE OF REVIEW
Mitochondrial disease is a heterogeneous group of energy metabolism disorders that present across all ages with a wide range of ocular or multisystemic manifestations. This review focuses on recent progress made toward understanding the various ophthalmologic manifestations of primary mitochondrial diseases and discusses the implications of mitochondrial dysfunction, placing particular emphasis on recent investigations into the pathogenesis and emerging therapies for mitochondrial-based ophthalmologic disorders.
RECENT FINDINGS
Novel pathogenic mitochondrial DNA mutations continue to be detected in diverse ethnic populations for primary mitochondrial ophthalmologic disorders that commonly affect the optic nerve, retina, and extraocular muscles. Promising antioxidant and gene therapy approaches are being actively investigated to treat these ophthalmologic manifestations, as in Leber's hereditary optic neuropathy. Mitochondrial dysfunction is also increasingly implicated in common ophthalmologic disorders of aging, including diabetic retinopathy, age-related macular degeneration, and glaucoma. Several proteins recently recognized to play a role in the mitochondrial oxidative stress response within retinal cells, such as prohibitin and MMP2, may serve as novel biomarkers and therapeutic targets for common ophthalmologic disorders. Therapies that inhibit mitochondrial function and induce apoptosis within tumor cells, such as EDL-155 and curcumin, may offer novel therapeutic agents for ocular neoplasms such as retinoblastoma and uveal melanoma.
SUMMARY
Primary mitochondrial genetic disease manifestations can involve almost all aspects of the eye. Mitochondrial dysfunction is increasingly recognized as playing a causative role in the common ophthalmologic disorders in aging. This understanding has unleashed a range of emerging therapeutic approaches for mitochondrial-based ophthalmologic disorders directed at optimizing mitochondrial function.
Topics: Aging; DNA, Mitochondrial; Eye Diseases; Eye Neoplasms; Female; Genetic Therapy; Humans; Macular Degeneration; Male; Matrix Metalloproteinase 2; Mitochondrial Diseases; Mutation; Ophthalmoplegia; Optic Neuropathy, Ischemic; Retinitis Pigmentosa
PubMed: 21730846
DOI: 10.1097/ICU.0b013e328349419d -
EMBO Molecular Medicine Oct 2015This commentary inaugurates a new review series in focused on mitochondrial diseases. This area of medicine, which actually encompasses most disease areas, has long...
This commentary inaugurates a new review series in focused on mitochondrial diseases. This area of medicine, which actually encompasses most disease areas, has long since come of age and is now positioned for the next leap toward the development of effective therapies. The aims of the review series are to offer a comprehensive overview of this exciting area of medicine and research and to provide timely discussions for clinicians and investigators on the new discoveries elucidating how mitochondrial metabolism contributes to an expanding group of complex, heterogeneous, and difficult-to-tackle diseases.
Topics: Genes, Mitochondrial; Humans; Mitochondria; Mitochondrial Diseases
PubMed: 26194910
DOI: 10.15252/emmm.201505350 -
The Journal of Pathology Jul 2021Mitochondria play essential roles in numerous metabolic pathways including the synthesis of adenosine triphosphate through oxidative phosphorylation. Clinically,... (Review)
Review
Mitochondria play essential roles in numerous metabolic pathways including the synthesis of adenosine triphosphate through oxidative phosphorylation. Clinically, mitochondrial diseases occur when there is mitochondrial dysfunction - manifesting at any age and affecting any organ system; tissues with high energy requirements, such as muscle and the brain, are often affected. The clinical heterogeneity is parallel to the degree of genetic heterogeneity associated with mitochondrial dysfunction. Around 10% of human genes are predicted to have a mitochondrial function, and defects in over 300 genes are reported to cause mitochondrial disease. Some involve the mitochondrial genome (mtDNA), but the vast majority occur within the nuclear genome. Except for a few specific genetic defects, there remains no cure for mitochondrial diseases, which means that a genetic diagnosis is imperative for genetic counselling and the provision of reproductive options for at-risk families. Next-generation sequencing strategies, particularly exome and whole-genome sequencing, have revolutionised mitochondrial diagnostics such that the traditional muscle biopsy has largely been replaced with a minimally-invasive blood sample for an unbiased approach to genetic diagnosis. Where these genomic approaches have not identified a causative defect, or where there is insufficient support for pathogenicity, additional functional investigations are required. The application of supplementary 'omics' technologies, including transcriptomics, proteomics, and metabolomics, has the potential to greatly improve diagnostic strategies. This review aims to demonstrate that whilst a molecular diagnosis can be achieved for many cases through next-generation sequencing of blood DNA, the use of patient tissues and an integrated, multidisciplinary multi-omics approach is pivotal for the diagnosis of more challenging cases. Moreover, the analysis of clinically relevant tissues from affected individuals remains crucial for understanding the molecular mechanisms underlying mitochondrial pathology. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
Topics: Animals; Genomics; Humans; Metabolomics; Mitochondria; Mitochondrial Diseases; Proteomics
PubMed: 33586140
DOI: 10.1002/path.5641