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Apoptosis in mitochondrial encephalomyopathies with mitochondrial DNA mutations: a potential pathogenic mechanism
M Mirabella1, S Di Giovanni, G Silvestri
1Institute of Neurology, Catholic University, Rome, Italy.
Abstract:
Mitochondrial encephalomyopathies caused by mitochondrial DNA (mtDNA) defects are a genetically and phenotypically heterogeneous group of disorders. The site, percentage and distribution of mutations do not explain the overall clinical heterogeneity that is found. Apoptosis (programmed cell death) is an evolutionarily conserved mechanism that is essential for tissue development and homeostasis. Dysregulation of apoptosis has been implicated in the pathogenesis of various human diseases, such as cancer and autoimmune and neurodegenerative disorders. Recent in vitro evidence has indicated the central role of mitochondria in the apoptotic process. We investigated the occurrence of apoptosis in muscle biopsies of 36 patients carrying different mtDNA mutations and four patients with inclusion body myositis and mitochondrial abnormalities. Apoptotic features, mainly localized in cytochrome c oxidase-negative fibres, were observed in muscle fibres of patients carrying a high percentage of single mtDNA deletions (>40%) and of tRNA point mutations (>70%). By contrast, no apoptotic changes were observed in inclusion body myositis and in patients carrying mutations of mtDNA structural genes. Our study suggests that apoptosis is not simply a means whereby cells with dysfunctional mitochondria are eliminated, but that it seems to play a role in the pathogenesis of mitochondrial disorders associated with mtDNA defects affecting mitochondrial protein synthesis. The imbalance and relative abundances of nuclear-encoded and mtDNA-encoded subunits may favour cytochrome c inactivation and release. Cytochrome c, together with respiratory chain dysfunction, could activate apoptotic pathways that, in turn, inhibit the rate of mitochondrial translation and the importation of nuclear-encoded mitochondrial protein precursors. This vicious circle may amplify the biochemical defects and tissue damage and contribute to the modulation of clinical features.
Insights
Apoptosis plays a role in mitochondrial encephalomyopathies caused by mitochondrial DNA (mtDNA) defects. This programmed cell death mechanism contributes to disease pathogenesis and clinical heterogeneity in patients with specific mtDNA mutations.
Area of Science:
- Molecular Biology
- Genetics
- Cell Biology
- Neuroscience
Background:
- Mitochondrial encephalomyopathies, caused by mitochondrial DNA (mtDNA) mutations, exhibit significant genetic and phenotypic heterogeneity.
- Apoptosis (programmed cell death) is a critical cellular process implicated in various diseases, with mitochondria playing a central role.
- The precise mechanisms driving the clinical heterogeneity in mtDNA disorders remain incompletely understood.
Purpose of the Study:
- To investigate the occurrence and role of apoptosis in muscle biopsies from patients with various mitochondrial DNA (mtDNA) mutations.
- To explore the relationship between apoptosis, specific mtDNA defects, and the pathogenesis of mitochondrial disorders.
Main Methods:
- Analysis of muscle biopsies from 36 patients with different mtDNA mutations and 4 patients with inclusion body myositis.
- Assessment of apoptotic features, particularly in cytochrome c oxidase-negative muscle fibers.
- Correlation of apoptotic findings with the percentage and type of mitochondrial DNA mutations (deletions, tRNA point mutations, structural gene mutations).
Main Results:
- Apoptotic features were observed in muscle fibers of patients with high percentages of single mtDNA deletions (>40%) and tRNA point mutations (>70%).
- No significant apoptotic changes were detected in inclusion body myositis or in patients with mutations in mtDNA structural genes.
- These findings suggest apoptosis is linked to specific mtDNA defects affecting mitochondrial protein synthesis.
Conclusions:
- Apoptosis is implicated in the pathogenesis of mitochondrial disorders associated with mtDNA defects impacting protein synthesis, not just as a cell elimination mechanism.
- An imbalance in mitochondrial protein subunits may trigger cytochrome c release, activating apoptotic pathways that exacerbate biochemical defects and tissue damage.
- This process may contribute to the modulation of clinical features and heterogeneity observed in mitochondrial encephalomyopathies.