Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Defects of the respiratory chain carrying out oxidative phosphorylation (OXPHOS) are the biochemical hallmark of human mitochondrial disorders. Faulty OXPHOS can be due to mutations in either nuclear or mitochondrial genes, that are involved in the synthesis of individual respiratory subunits or in their post-translational control. The most common mitochondrial disorder of infancy and childhood is Leigh's syndrome, a severe encephalopathy, often associated with a defect of cytochrome c oxidase (COX). In order to demonstrate which genome is primarily involved in COX-deficient (COX(-))-Leigh's syndrome, we generated two lines of transmitochondrial cybrids. The first was obtained by fusing nuclear DNA-less cytoplasts derived from normal fibroblasts, with mitochondrial DNA-less (rho degree) transformant fibroblasts derived from a patient with COX(-))-Leigh's syndrome. The second cybrid line was obtained by fusing rho degree cells derived from 143B.TK- human osteosarcoma cells, with cytoplasts derived from the same patient. The first cybrid line showed a specific and severe COX(-) phenotype, while in the second all the respiratory chain complexes, including COX, were normal. These results indicate that the COX defect in our patient is due to a mutation of a nuclear gene. The use of cybrids obtained from 'customized', patient-derived rho degree cells can have wide applications in the identification of respiratory chain defects originated by nuclear DNA-encoded mutations, and in the study of nuclear DNA-mitochondrial DNA interactions.
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PMID:Nuclear DNA origin of cytochrome c oxidase deficiency in Leigh's syndrome: genetic evidence based on patient's-derived rho degrees transformants. 858 77

The key role of mitochondria in the apoptotic process is well understood, but not many data are available regarding the specific role of mitochondrial DNA mutations in determining cell fate. We investigated whether two mitochondrial DNA mutations (L217R and L156R) associated with maternally-inherited Leigh syndrome may play a specific role in triggering the apoptotic cascade. Considering that different nuclear genetic factors may influence the expression of mtDNA mutations, we used a 143BTK(-) osteosarcoma cell line deprived from its own mtDNA in order to insert mutated mtDNAs. Analysis of mitochondrial features in these cybrids indicated that both mitochondrial DNA mutations produced evidence of biochemical, functional and ultrastructural modifications of mitochondria, and that these modifications were associated with an increased apoptotic proneness. Cybrids were highly susceptible to two different apoptotic stimuli, tumour necrosis factor-alpha and Staurosporin. The mechanism involved was the mitochondrial 'intrinsic' pathway, i.e. the caspase 9-driven cascade. More importantly, our results also indicated that the polarization state of the mitochondrial membrane, i.e. a constitutive hyperpolarization detected in cybrid clones, played a specific role. Interestingly, the different effects of the two mutations in terms of susceptibility to apoptosis probably reflect the deeper bioenergetic defect associated with the L217R mutation. This work provides the first evidence that hyperpolarization of mitochondria may be a 'risk factor' for cells with a deep ATPase dysfunction, such as cells from patients with maternally-inherited Leigh syndrome.
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PMID:Maternally-inherited Leigh syndrome-related mutations bolster mitochondrial-mediated apoptosis. 1522 5