Nuclear DNA origin of cytochrome c oxidase deficiency in Leigh's syndrome: genetic evidence based on patient's-derived rho degrees transformants.

TitleNuclear DNA origin of cytochrome c oxidase deficiency in Leigh's syndrome: genetic evidence based on patient's-derived rho degrees transformants.
Publication TypeJournal Article
Year of Publication1995
AuthorsTiranti, V, Munaro, M, Sandonà, D, Lamantea, E, Rimoldi, M, DiDonato, S, Bisson, R, Zeviani, M
JournalHum Mol Genet
Volume4
Issue11
Pagination2017-23
Date Published1995 Nov
ISSN0964-6906
KeywordsCell Line, Cell Nucleus, Cytochrome-c Oxidase Deficiency, DNA, Electron Transport, Electron Transport Complex IV, Female, Fibroblasts, Fluorescent Antibody Technique, Humans, Hybrid Cells, Leigh Disease, Mitochondria, Oxidative Phosphorylation, Transformation, Genetic, Tumor Cells, Cultured
Abstract

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.

DOI10.1093/hmg/4.11.2017
Alternate JournalHum. Mol. Genet.
Citation Key10.1093/hmg/4.11.2017
PubMed ID8589677
Grant List456 / / Telethon / Italy