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Pathological mechanisms underlying single large‐scale mitochondrial DNA deletions
OBJECTIVE: Single, large‐scale deletions in mitochondrial DNA (mtDNA) are a common cause of mitochondrial disease. This study aimed to investigate the relationship between the genetic defect and molecular phenotype to improve understanding of pathogenic mechanisms associated with single, large‐scale...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5893934/ https://www.ncbi.nlm.nih.gov/pubmed/29283441 http://dx.doi.org/10.1002/ana.25127 |
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author | Rocha, Mariana C. Rosa, Hannah S. Grady, John P. Blakely, Emma L. He, Langping Romain, Nadine Haller, Ronald G. Newman, Jane McFarland, Robert Ng, Yi Shiau Gorman, Grainne S. Schaefer, Andrew M. Tuppen, Helen A. Taylor, Robert W. Turnbull, Doug M. |
author_facet | Rocha, Mariana C. Rosa, Hannah S. Grady, John P. Blakely, Emma L. He, Langping Romain, Nadine Haller, Ronald G. Newman, Jane McFarland, Robert Ng, Yi Shiau Gorman, Grainne S. Schaefer, Andrew M. Tuppen, Helen A. Taylor, Robert W. Turnbull, Doug M. |
author_sort | Rocha, Mariana C. |
collection | PubMed |
description | OBJECTIVE: Single, large‐scale deletions in mitochondrial DNA (mtDNA) are a common cause of mitochondrial disease. This study aimed to investigate the relationship between the genetic defect and molecular phenotype to improve understanding of pathogenic mechanisms associated with single, large‐scale mtDNA deletions in skeletal muscle. METHODS: We investigated 23 muscle biopsies taken from adult patients (6 males/17 females with a mean age of 43 years) with characterized single, large‐scale mtDNA deletions. Mitochondrial respiratory chain deficiency in skeletal muscle biopsies was quantified by immunoreactivity levels for complex I and complex IV proteins. Single muscle fibers with varying degrees of deficiency were selected from 6 patient biopsies for determination of mtDNA deletion level and copy number by quantitative polymerase chain reaction. RESULTS: We have defined 3 “classes” of single, large‐scale deletion with distinct patterns of mitochondrial deficiency, determined by the size and location of the deletion. Single fiber analyses showed that fibers with greater respiratory chain deficiency harbored higher levels of mtDNA deletion with an increase in total mtDNA copy number. For the first time, we have demonstrated that threshold levels for complex I and complex IV deficiency differ based on deletion class. INTERPRETATION: Combining genetic and immunofluorescent assays, we conclude that thresholds for complex I and complex IV deficiency are modulated by the deletion of complex‐specific protein‐encoding genes. Furthermore, removal of mt‐tRNA genes impacts specific complexes only at high deletion levels, when complex‐specific protein‐encoding genes remain. These novel findings provide valuable insight into the pathogenic mechanisms associated with these mutations. Ann Neurol 2018;83:115–130 |
format | Online Article Text |
id | pubmed-5893934 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-58939342018-04-18 Pathological mechanisms underlying single large‐scale mitochondrial DNA deletions Rocha, Mariana C. Rosa, Hannah S. Grady, John P. Blakely, Emma L. He, Langping Romain, Nadine Haller, Ronald G. Newman, Jane McFarland, Robert Ng, Yi Shiau Gorman, Grainne S. Schaefer, Andrew M. Tuppen, Helen A. Taylor, Robert W. Turnbull, Doug M. Ann Neurol Research Articles OBJECTIVE: Single, large‐scale deletions in mitochondrial DNA (mtDNA) are a common cause of mitochondrial disease. This study aimed to investigate the relationship between the genetic defect and molecular phenotype to improve understanding of pathogenic mechanisms associated with single, large‐scale mtDNA deletions in skeletal muscle. METHODS: We investigated 23 muscle biopsies taken from adult patients (6 males/17 females with a mean age of 43 years) with characterized single, large‐scale mtDNA deletions. Mitochondrial respiratory chain deficiency in skeletal muscle biopsies was quantified by immunoreactivity levels for complex I and complex IV proteins. Single muscle fibers with varying degrees of deficiency were selected from 6 patient biopsies for determination of mtDNA deletion level and copy number by quantitative polymerase chain reaction. RESULTS: We have defined 3 “classes” of single, large‐scale deletion with distinct patterns of mitochondrial deficiency, determined by the size and location of the deletion. Single fiber analyses showed that fibers with greater respiratory chain deficiency harbored higher levels of mtDNA deletion with an increase in total mtDNA copy number. For the first time, we have demonstrated that threshold levels for complex I and complex IV deficiency differ based on deletion class. INTERPRETATION: Combining genetic and immunofluorescent assays, we conclude that thresholds for complex I and complex IV deficiency are modulated by the deletion of complex‐specific protein‐encoding genes. Furthermore, removal of mt‐tRNA genes impacts specific complexes only at high deletion levels, when complex‐specific protein‐encoding genes remain. These novel findings provide valuable insight into the pathogenic mechanisms associated with these mutations. Ann Neurol 2018;83:115–130 John Wiley and Sons Inc. 2018-01-24 2018-01 /pmc/articles/PMC5893934/ /pubmed/29283441 http://dx.doi.org/10.1002/ana.25127 Text en © 2017 The Authors Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Articles Rocha, Mariana C. Rosa, Hannah S. Grady, John P. Blakely, Emma L. He, Langping Romain, Nadine Haller, Ronald G. Newman, Jane McFarland, Robert Ng, Yi Shiau Gorman, Grainne S. Schaefer, Andrew M. Tuppen, Helen A. Taylor, Robert W. Turnbull, Doug M. Pathological mechanisms underlying single large‐scale mitochondrial DNA deletions |
title | Pathological mechanisms underlying single large‐scale mitochondrial DNA deletions |
title_full | Pathological mechanisms underlying single large‐scale mitochondrial DNA deletions |
title_fullStr | Pathological mechanisms underlying single large‐scale mitochondrial DNA deletions |
title_full_unstemmed | Pathological mechanisms underlying single large‐scale mitochondrial DNA deletions |
title_short | Pathological mechanisms underlying single large‐scale mitochondrial DNA deletions |
title_sort | pathological mechanisms underlying single large‐scale mitochondrial dna deletions |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5893934/ https://www.ncbi.nlm.nih.gov/pubmed/29283441 http://dx.doi.org/10.1002/ana.25127 |
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