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Mitochondrial encephalomyopathies
1Department of Pathology, Sahlgrenska University Hospital, Goteborg, Sweden. anders.oldfors@path.gu.se
Insights
Mitochondrial encephalomyopathies, caused by defective oxidative phosphorylation (OXPHOS), impact the nervous system and muscles. Research identifies over 100 mitochondrial DNA mutations and nuclear DNA gene mutations contributing to these complex OXPHOS disorders.
Area of Science:
- Biochemistry
- Genetics
- Neurology
Background:
- Mitochondrial encephalomyopathies result from impaired oxidative phosphorylation (OXPHOS), affecting neurological and muscular functions.
- These disorders are significant neurometabolic conditions in children and adults, with a notable incidence rate.
- Over 100 mitochondrial DNA (mtDNA) mutations and numerous nuclear DNA (nDNA) gene mutations have been identified as causes.
Purpose of the Study:
- To review the genetic basis of mitochondrial encephalomyopathies.
- To highlight the diverse range of mutations in both mtDNA and nDNA.
- To discuss the implications of these mutations on OXPHOS and disease pathophysiology.
Main Methods:
- Literature review of reported mutations in mitochondrial and nuclear DNA.
- Analysis of genotype-phenotype correlations in OXPHOS disorders.
- Discussion of the role of animal models in studying disease mechanisms.
Main Results:
- Identification of over 100 pathogenic mtDNA mutations (point mutations, deletions).
- Discovery of nDNA mutations affecting respiratory chain subunits and assembly proteins.
- Association of nuclear genes with mtDNA maintenance, leading to deletions or copy number reduction.
Conclusions:
- Mitochondrial encephalomyopathies arise from a complex interplay of genetic defects in both mtDNA and nDNA.
- Understanding genotype-phenotype correlations remains challenging but is advancing.
- New animal models are crucial for further elucidating OXPHOS disorder pathophysiology.
Abstract:
Mitochondrial encephalomyopathies are diseases caused by defective oxidative phosphorylation (OXPHOS), and affect the nervous system and/or skeletal muscle. They have emerged as a major entity among the neurometabolic diseases of childhood with an incidence of 1 in 11,000 children, and also have a high prevalence in adults. The first pathogenic mutation of human mitochondrial DNA (mtDNA) was discovered in 1988. Since then more than 100 mutations of mtDNA have been reported, including point mutations of genes encoding transfer RNA, ribosomal RNA, and proteins, as well as large-scale deletions. The first nuclear-DNA gene mutation causing OXPHOS disease was described in 1995. Mutations in nuclear genes may affect the respiratory chain by various mechanisms. Pathogenic mutations of nuclear-DNA-encoded subunits of complex I and II have been demonstrated as have mutations of respiratory chain assembly proteins. Several nuclear genes associated with mtDNA maintenance have been found to be associated with mitochondrial disorders since mutations in these genes predispose to multiple mtDNA deletions and/or reduced copy number of mtDNA. The genotype-phenotype correlation is not yet entirely clear, but new animal models will enhance our ability to study the pathophysiology of OXPHOS disorders.