Impact of the mitochondrial genetic background in complex III deficiency.

<h4>Background</h4>In recent years clinical evidence has emphasized the importance of the mtDNA genetic background that hosts a primary pathogenic mutation in the clinical expression of mitochondrial disorders, but little experimental confirmation has been provided. We have analyzed the...

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Autores principales:	Mari Carmen Gil Borlado, David Moreno Lastres, Maritza Gonzalez Hoyuela, Maria Moran, Alberto Blazquez, Rosa Pello, Lorena Marin Buera, Toni Gabaldon, Juan Jose Garcia Peñas, Miguel A Martín, Joaquin Arenas, Cristina Ugalde
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7c6c727f63f149498e750aef37a1f2ea
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spelling	oai:doaj.org-article:7c6c727f63f149498e750aef37a1f2ea2021-11-18T06:35:02ZImpact of the mitochondrial genetic background in complex III deficiency.1932-620310.1371/journal.pone.0012801https://doaj.org/article/7c6c727f63f149498e750aef37a1f2ea2010-09-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20862300/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>In recent years clinical evidence has emphasized the importance of the mtDNA genetic background that hosts a primary pathogenic mutation in the clinical expression of mitochondrial disorders, but little experimental confirmation has been provided. We have analyzed the pathogenic role of a novel homoplasmic mutation (m.15533 A>G) in the cytochrome b (MT-CYB) gene in a patient presenting with lactic acidosis, seizures, mild mental delay, and behaviour abnormalities.<h4>Methodology</h4>Spectrophotometric analyses of the respiratory chain enzyme activities were performed in different tissues, the whole muscle mitochondrial DNA of the patient was sequenced, and the novel mutation was confirmed by PCR-RFLP. Transmitochondrial cybrids were constructed to confirm the pathogenicity of the mutation, and assembly/stability studies were carried out in fibroblasts and cybrids by means of mitochondrial translation inhibition in combination with blue native gel electrophoresis.<h4>Principal findings</h4>Biochemical analyses revealed a decrease in respiratory chain complex III activity in patient's skeletal muscle, and a combined enzyme defect of complexes III and IV in fibroblasts. Mutant transmitochondrial cybrids restored normal enzyme activities and steady-state protein levels, the mutation was mildly conserved along evolution, and the proband's mother and maternal aunt, both clinically unaffected, also harboured the homoplasmic mutation. These data suggested a nuclear genetic origin of the disease. However, by forcing the de novo functioning of the OXPHOS system, a severe delay in the biogenesis of the respiratory chain complexes was observed in the mutants, which demonstrated a direct functional effect of the mitochondrial genetic background.<h4>Conclusions</h4>Our results point to possible pitfalls in the detection of pathogenic mitochondrial mutations, and highlight the role of the genetic mtDNA background in the development of mitochondrial disorders.Mari Carmen Gil BorladoDavid Moreno LastresMaritza Gonzalez HoyuelaMaria MoranAlberto BlazquezRosa PelloLorena Marin BueraToni GabaldonJuan Jose Garcia PeñasMiguel A MartínJoaquin ArenasCristina UgaldePublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 5, Iss 9 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Mari Carmen Gil Borlado David Moreno Lastres Maritza Gonzalez Hoyuela Maria Moran Alberto Blazquez Rosa Pello Lorena Marin Buera Toni Gabaldon Juan Jose Garcia Peñas Miguel A Martín Joaquin Arenas Cristina Ugalde Impact of the mitochondrial genetic background in complex III deficiency.
description	<h4>Background</h4>In recent years clinical evidence has emphasized the importance of the mtDNA genetic background that hosts a primary pathogenic mutation in the clinical expression of mitochondrial disorders, but little experimental confirmation has been provided. We have analyzed the pathogenic role of a novel homoplasmic mutation (m.15533 A>G) in the cytochrome b (MT-CYB) gene in a patient presenting with lactic acidosis, seizures, mild mental delay, and behaviour abnormalities.<h4>Methodology</h4>Spectrophotometric analyses of the respiratory chain enzyme activities were performed in different tissues, the whole muscle mitochondrial DNA of the patient was sequenced, and the novel mutation was confirmed by PCR-RFLP. Transmitochondrial cybrids were constructed to confirm the pathogenicity of the mutation, and assembly/stability studies were carried out in fibroblasts and cybrids by means of mitochondrial translation inhibition in combination with blue native gel electrophoresis.<h4>Principal findings</h4>Biochemical analyses revealed a decrease in respiratory chain complex III activity in patient's skeletal muscle, and a combined enzyme defect of complexes III and IV in fibroblasts. Mutant transmitochondrial cybrids restored normal enzyme activities and steady-state protein levels, the mutation was mildly conserved along evolution, and the proband's mother and maternal aunt, both clinically unaffected, also harboured the homoplasmic mutation. These data suggested a nuclear genetic origin of the disease. However, by forcing the de novo functioning of the OXPHOS system, a severe delay in the biogenesis of the respiratory chain complexes was observed in the mutants, which demonstrated a direct functional effect of the mitochondrial genetic background.<h4>Conclusions</h4>Our results point to possible pitfalls in the detection of pathogenic mitochondrial mutations, and highlight the role of the genetic mtDNA background in the development of mitochondrial disorders.
format	article
author	Mari Carmen Gil Borlado David Moreno Lastres Maritza Gonzalez Hoyuela Maria Moran Alberto Blazquez Rosa Pello Lorena Marin Buera Toni Gabaldon Juan Jose Garcia Peñas Miguel A Martín Joaquin Arenas Cristina Ugalde
author_facet	Mari Carmen Gil Borlado David Moreno Lastres Maritza Gonzalez Hoyuela Maria Moran Alberto Blazquez Rosa Pello Lorena Marin Buera Toni Gabaldon Juan Jose Garcia Peñas Miguel A Martín Joaquin Arenas Cristina Ugalde
author_sort	Mari Carmen Gil Borlado
title	Impact of the mitochondrial genetic background in complex III deficiency.
title_short	Impact of the mitochondrial genetic background in complex III deficiency.
title_full	Impact of the mitochondrial genetic background in complex III deficiency.
title_fullStr	Impact of the mitochondrial genetic background in complex III deficiency.
title_full_unstemmed	Impact of the mitochondrial genetic background in complex III deficiency.
title_sort	impact of the mitochondrial genetic background in complex iii deficiency.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/7c6c727f63f149498e750aef37a1f2ea
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Impact of the mitochondrial genetic background in complex III deficiency.

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