Related Experiment Videos
Lack of apoptosis in mitochondrial encephalomyopathies
M Sciacco1, G Fagiolari, C Lamperti
1Centro Dino Ferrari, Istituto di Clinica Neurologica, University of Milan, Ospedale Maggiore IRCCS, Milan, Italy.
Background/Objective:
Apoptosis, or programmed cell death, is an evolutionary conserved mechanism essential for morphogenesis and tissue homeostasis, but it plays an important role also in pathologic conditions, including neurologic disorders. Its execution pathway is critically regulated at the mitochondrial level. Evidence of apoptosis in muscle specimens was investigated in patients with genetically defined mitochondrial encephalomyopathies.
Methods:
Thirty-three muscle biopsies from patients with genotypically different mitochondrial diseases (single and multiple deletions, A3243G/A8344G point mutations of the mitochondrial DNA) were studied. The terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) reaction was used as a marker of nuclear DNA fragmentation, as well as antibodies against pro- (Fas) or anti- (Bcl-2) apoptotic factors. Also, because one hallmark of apoptosis is morphologic, ultrastructural studies were performed on skeletal muscle from 18 of 33 patients, examining both phenotypically normal and ragged red fibers.
Results:
In all muscle biopsies, no significant expression of either pro (Fas) and inhibiting (Bcl-2) apoptosis-related proteins was found, nor TUNEL positivity. This latter finding is confirmed by lack of morphologic evidence of apoptosis in all the fibers examined at the ultrastructural level.
Conclusion:
The authors' findings suggest that genetically determined defects of oxidative phosphorylation do not induce the apoptotic process and that apoptosis is not involved in the pathogenesis of mitochondrial disorders.
Insights
This study found that apoptosis, or programmed cell death, is not involved in mitochondrial disorders. Muscle biopsies from patients with genetic mitochondrial diseases showed no evidence of apoptosis, suggesting it does not contribute to disease pathogenesis.
Area of Science:
- Cell Biology
- Neurogenetics
- Mitochondrial Medicine
Background:
- Apoptosis (programmed cell death) is crucial for development and homeostasis, but also implicated in neurological disorders.
- Mitochondria play a key role in regulating the execution pathway of apoptosis.
- Evidence of apoptosis in muscle tissue of patients with mitochondrial encephalomyopathies was investigated.
Purpose of the Study:
- To investigate the presence and role of apoptosis in genetically defined mitochondrial encephalomyopathies.
- To determine if defects in oxidative phosphorylation trigger the apoptotic process.
- To assess the involvement of apoptosis in the pathogenesis of mitochondrial disorders.
Main Methods:
- Analysis of 33 muscle biopsies from patients with various mitochondrial DNA defects (deletions, point mutations).
- Utilized TUNEL assay for nuclear DNA fragmentation and antibodies for apoptotic factors (Fas, Bcl-2).
- Performed ultrastructural studies on skeletal muscle fibers (normal and ragged red) from 18 patients.
Main Results:
- No significant expression of pro-apoptotic (Fas) or anti-apoptotic (Bcl-2) proteins was detected in any biopsy.
- TUNEL positivity, indicating nuclear DNA fragmentation, was absent in all muscle samples.
- Ultrastructural examination revealed no morphologic evidence of apoptosis in any muscle fibers.
Conclusions:
- Genetically determined defects in oxidative phosphorylation do not appear to induce apoptosis.
- Apoptosis is not a significant factor in the pathogenesis of mitochondrial disorders.
- These findings challenge the presumed role of apoptosis in the progression of mitochondrial diseases.