Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
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.
 ...
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.
 ...
PMID:Mitochondrial DNA mutation and depletion increase the susceptibility of human cells to apoptosis. 1512 91

Chronic progressive external ophthalmoplegia (CPEO) syndrome is one of the mitochondrial diseases caused by large-scale deletions in mitochondrial DNA (mtDNA) that impair the respiratory function of mitochondria and result in decreased production of ATP in affected tissues. In order to investigate whether CPEO-associated mtDNA mutations (i.e., 4,366-bp and 4,977-bp large-scale deletions) render human cells more vulnerable to apoptosis, we constructed cybrids carrying the deleted mtDNA. Assays for cell viability, DNA fragmentation, cytochrome c release, and caspase 3 activation revealed that UV irradiation at 20 J/m2 triggered apoptosis in all the cybrids. This treatment also produced elevated intracellular levels of reactive oxygen species (ROS). The rate of UV-induced cell death was more pronounced in the cybrids harboring mtDNA deletions than in the control cybrid with wild-type mtDNA. Subsequently, we evaluated the effect of coenzyme Q10 on the UV-triggered apoptosis. The results showed that after pretreatment of the cybrids with 100 microM coenzyme Q10 the UV-induced cell damage (i.e., ROS production and activation of caspase 3) was significantly reduced. Taken together, these findings suggest that large-scale deletions of mtDNA increased the susceptibility of human cells to the UV-triggered apoptosis and that coenzyme Q10 mitigated the damage; hence, it might potentially serve as a therapeutic agent to treat mitochondrial diseases resulting from mtDNA deletions.
 ...
PMID:Attenuation of UV-induced apoptosis by coenzyme Q10 in human cells harboring large-scale deletion of mitochondrial DNA. 1596 89