Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Over the past few years, many studies have been done on the apoptotic involvement in muscle fiber degeneration in various myopathies, but the occurrence of apoptosis in muscles of mitochondrial encephalomyopathies is still controversial. To confirm whether apoptotic processes are truly related to muscle fiber degeneration in mitochondrial encephalomyopathies, we performed the TUNEL method not only at the light microscopic (LM) but also at the electron microscopic (EM) level for muscles of five MELAS, five CPEO and five MERRF patients and five control muscles. Immunohistochemical studies of Bcl-2, Bax, cytochrome c, Apaf-1, activated caspase-3 and human inhibitor of apoptosis protein XIAP, and immunoblotting of Apaf-1 and XIAP were also carried out. In LM-TUNEL, MELAS, CPEO and MERRF patients had only very small numbers of TUNEL-positive myonuclei: 0.13+/-0.10%, 0.15+/-0.14% and 0.04+/-0.09%, respectively. Almost all of them were seen in ragged-red fibers (RRFs). EM-TUNEL showed no significant increase of DNA fragmentation in RRFs despite mild peripheral chromatin condensation. However, Bax and Apaf-1 expression and cytochrome c release from mitochondria were seen in RRFs. Caspase-3 activation was confirmed in 9.0+/-3.7%, 12.0+/-4.4% and 12.4+/-3.8% of RRFs in MELAS, CPEO and MERRF, respectively, but not in control muscles. Almost all RRFs showed sarcoplasmic expression of XIAP. Thus, there is a possibility that, although apoptotic reactions started in muscles of mitochondrial encephalomyopathies, their execution is rarely completed. Sarcoplasmic expression of XIAP probably leads to the suspension of the apoptotic process in mitochondrial encephalomyopathies.
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PMID:Apoptosis is suspended in muscle of mitochondrial encephalomyopathies. 1201 84

Mitochondrial diseases, such as MELAS, MERRF, and CPEO syndromes, are associated with specific point mutations or large-scale deletions of mitochondrial DNA (mtDNA), which impair mitochondrial respiratory functions and result in decreased production of ATP in affected tissues. Recently, mitochondria have been recognized to act as key players in the regulation of cell death. To investigate whether a pathogenic mutation of mtDNA exerts any effect on the process of apoptosis of human cells, we constructed a series of cybrid human cells harboring different proportions of mtDNA with the A3243G or the A8344G transition, or with the 4,977-bp deletion, by cytoplasmic fusion of patients' skin fibroblasts with mtDNA-depleted rho(0) cells of an immortal human osteosarcoma cell line (143B). We observed that the decrease in cell viability upon staurosporine treatment or exposure to ultraviolet (UV) irradiation was more pronounced in the cybrids harboring high levels of mutated mtDNA compared with the control cybrids. Using DNA fragmentation analysis, we found that the cell death induced by treatment with 100 nM staurosporine or by exposure to UV irradiation at 20 J/m(2) was caused by apoptosis, not necrosis. Moreover, we demonstrated activation of caspase 3 by Western blot and enhanced release of cytochrome c after 100 nM staurosporine treatment or 20 J/m(2) UV irradiation of the cybrids harboring high levels of the three mtDNA mutations. Furthermore, as compared with parental osteosarcoma 143B cells, the rho(0) cells were found to be more susceptible to apoptosis, which was accompanied by caspase 3 activation and cytochrome c release. This indicates that mtDNA plays an important role in the regulation of apoptosis in human cells. Taken together, these findings suggest that mutation and depletion of mtDNA increase the susceptibility of human cells to apoptosis triggered by exogenous stimuli such as UV irradiation or staurosporine.
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PMID:Mitochondrial DNA mutation and depletion increase the susceptibility of human cells to apoptosis. 1512 91

Increased susceptibility to apoptosis has been shown in many models of mitochondrial defects but its relevance to human diseases is still discussed. We addressed the presence of apoptosis in muscle from patients with mitochondrial DNA (mtDNA) disorders. Taking advantage of the mosaic pattern of muscle morphological anomalies associated with heteroplasmic mtDNA alterations, we have used an in situ approach to address the relationship between apoptosis and respiratory defect, mitochondrial proliferation and mutation load. Different patterns of mitochondrial morphological alterations were provided by the analysis of muscles with large mtDNA deletion (16 cases) or with the MELAS mutation (4 cases). The patient's age at biopsy ranged from 0.4 to 66 years and the muscle mutant mtDNA proportion from 32 to 82%. Apoptotic muscle fibres were observed in a small proportion of muscle fibres of 16 out of the 20 biopsies by three different detection methods for different steps of apoptosis: caspase 3 activation, fragmentation of nuclear DNA [terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) assay] or overexpression of the pro-apoptotic factor Bax. Analysis of apoptotic features in parallel to cytochrome c oxidase (COX) and succinate dehydrogenase activity of more than 34,000 individual muscle fibres showed that apoptosis occurred only in muscle fibres with mitochondrial proliferation (ragged red fibres, RRF) irrespective of their COX activity. Molecular analyses of single muscle fibres evidenced that, as expected, the presence of COX defect was associated with higher proportion of mutant mtDNA and lower amount of normal mtDNA. Within COX-defective fibres, the presence of mitochondrial proliferation was associated with increase of the mtDNA content but without change in the ratio between normal and mutant mtDNA molecules, thus showing that mitochondrial proliferation was accompanied by similar amplification of normal and mutant mtDNA molecules. Within RRF, apoptosis was associated with higher mutation proportion, suggesting that it was provoked by severe respiratory defect in the same time as increased mitochondrial mass. In conclusion, apoptosis most probably contributes to mitochondrial pathology. It is tightly linked to mitochondrial proliferation and high mutation load. When considering training therapeutics, one will have to take into account the possibility to induce apoptosis in parallel to mitochondrial proliferation.
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PMID:Apoptosis in mitochondrial myopathies is linked to mitochondrial proliferation. 1653 64