Insights into the pathogenic character of a common NUBPL branch-site mutation associated with mitochondrial disease and complex I deficiency using a yeast model

SUMMARY Complex I deficiencies are the most common causes of mitochondrial disorders. They can result from mutations not only in the structural subunits but also in a growing number of known assembly factors. A branch-site mutation in the human gene encoding assembly factor NUBPL has recently been a...

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Main Authors:	Mateusz M. Wydro, Janneke Balk
Format:	Article
Language:	English
Published:	The Company of Biologists 2013-09-01
Series:	Disease Models & Mechanisms
Online Access:	http://dmm.biologists.org/content/6/5/1279

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spelling	doaj-fde6bd3ee3a5404cacc8063beed4dd022020-11-24T21:23:02ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112013-09-01651279128410.1242/dmm.012682012682Insights into the pathogenic character of a common NUBPL branch-site mutation associated with mitochondrial disease and complex I deficiency using a yeast modelMateusz M. WydroJanneke BalkSUMMARY Complex I deficiencies are the most common causes of mitochondrial disorders. They can result from mutations not only in the structural subunits but also in a growing number of known assembly factors. A branch-site mutation in the human gene encoding assembly factor NUBPL has recently been associated with mitochondrial encephalopathy and complex I deficiency in seven independent cases. Moreover, the mutation is present in 1.2% of European haplotypes. To investigate its pathogenicity, we have reconstructed the altered C-terminus that results from the branch-site mutation and frameshift in the homologous Ind1 protein in the respiratory yeast Yarrowia lipolytica. We demonstrate that the altered sequence did not affect IND1 mRNA stability, yet it led to a decrease in Ind1 protein level. The instability of mutant Ind1 resulted in a strong decrease in complex I activity and caused slow growth, resembling the phenotype of the deletion strain of IND1. The presented data confirms the deleterious impact of the altered C-terminus resulting from the branch-site mutation. Furthermore, our approach demonstrates the great potential of Y. lipolytica as a model to investigate complex I deficiencies, especially in cases with genetic complexity.http://dmm.biologists.org/content/6/5/1279
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Mateusz M. Wydro Janneke Balk
spellingShingle	Mateusz M. Wydro Janneke Balk Insights into the pathogenic character of a common NUBPL branch-site mutation associated with mitochondrial disease and complex I deficiency using a yeast model Disease Models & Mechanisms
author_facet	Mateusz M. Wydro Janneke Balk
author_sort	Mateusz M. Wydro
title	Insights into the pathogenic character of a common NUBPL branch-site mutation associated with mitochondrial disease and complex I deficiency using a yeast model
title_short	Insights into the pathogenic character of a common NUBPL branch-site mutation associated with mitochondrial disease and complex I deficiency using a yeast model
title_full	Insights into the pathogenic character of a common NUBPL branch-site mutation associated with mitochondrial disease and complex I deficiency using a yeast model
title_fullStr	Insights into the pathogenic character of a common NUBPL branch-site mutation associated with mitochondrial disease and complex I deficiency using a yeast model
title_full_unstemmed	Insights into the pathogenic character of a common NUBPL branch-site mutation associated with mitochondrial disease and complex I deficiency using a yeast model
title_sort	insights into the pathogenic character of a common nubpl branch-site mutation associated with mitochondrial disease and complex i deficiency using a yeast model
publisher	The Company of Biologists
series	Disease Models & Mechanisms
issn	1754-8403 1754-8411
publishDate	2013-09-01
description	SUMMARY Complex I deficiencies are the most common causes of mitochondrial disorders. They can result from mutations not only in the structural subunits but also in a growing number of known assembly factors. A branch-site mutation in the human gene encoding assembly factor NUBPL has recently been associated with mitochondrial encephalopathy and complex I deficiency in seven independent cases. Moreover, the mutation is present in 1.2% of European haplotypes. To investigate its pathogenicity, we have reconstructed the altered C-terminus that results from the branch-site mutation and frameshift in the homologous Ind1 protein in the respiratory yeast Yarrowia lipolytica. We demonstrate that the altered sequence did not affect IND1 mRNA stability, yet it led to a decrease in Ind1 protein level. The instability of mutant Ind1 resulted in a strong decrease in complex I activity and caused slow growth, resembling the phenotype of the deletion strain of IND1. The presented data confirms the deleterious impact of the altered C-terminus resulting from the branch-site mutation. Furthermore, our approach demonstrates the great potential of Y. lipolytica as a model to investigate complex I deficiencies, especially in cases with genetic complexity.
url	http://dmm.biologists.org/content/6/5/1279
work_keys_str_mv	AT mateuszmwydro insightsintothepathogeniccharacterofacommonnubplbranchsitemutationassociatedwithmitochondrialdiseaseandcomplexideficiencyusingayeastmodel AT jannekebalk insightsintothepathogeniccharacterofacommonnubplbranchsitemutationassociatedwithmitochondrialdiseaseandcomplexideficiencyusingayeastmodel
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Insights into the pathogenic character of a common NUBPL branch-site mutation associated with mitochondrial disease and complex I deficiency using a yeast model

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