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Haploinsufficiency due to a novel ACO2 deletion causes mitochondrial dysfunction in fibroblasts from a patient with dominant optic nerve atrophy

ACO2 is a mitochondrial protein, which is critically involved in the function of the tricarboxylic acid cycle (TCA), the maintenance of iron homeostasis, oxidative stress defense and the integrity of mitochondrial DNA (mtDNA). Mutations in the ACO2 gene were identified in patients suffering from a b...

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Autores principales: Neumann, Marie Anne-Catherine, Grossmann, Dajana, Schimpf-Linzenbold, Simone, Dayan, Dana, Stingl, Katarina, Ben-Menachem, Reut, Pines, Ophry, Massart, François, Delcambre, Sylvie, Ghelfi, Jenny, Bohler, Jill, Strom, Tim, Kessel, Amit, Azem, Abdussalam, Schöls, Ludger, Grünewald, Anne, Wissinger, Bernd, Krüger, Rejko
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541502/
https://www.ncbi.nlm.nih.gov/pubmed/33028849
http://dx.doi.org/10.1038/s41598-020-73557-4
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author Neumann, Marie Anne-Catherine
Grossmann, Dajana
Schimpf-Linzenbold, Simone
Dayan, Dana
Stingl, Katarina
Ben-Menachem, Reut
Pines, Ophry
Massart, François
Delcambre, Sylvie
Ghelfi, Jenny
Bohler, Jill
Strom, Tim
Kessel, Amit
Azem, Abdussalam
Schöls, Ludger
Grünewald, Anne
Wissinger, Bernd
Krüger, Rejko
author_facet Neumann, Marie Anne-Catherine
Grossmann, Dajana
Schimpf-Linzenbold, Simone
Dayan, Dana
Stingl, Katarina
Ben-Menachem, Reut
Pines, Ophry
Massart, François
Delcambre, Sylvie
Ghelfi, Jenny
Bohler, Jill
Strom, Tim
Kessel, Amit
Azem, Abdussalam
Schöls, Ludger
Grünewald, Anne
Wissinger, Bernd
Krüger, Rejko
author_sort Neumann, Marie Anne-Catherine
collection PubMed
description ACO2 is a mitochondrial protein, which is critically involved in the function of the tricarboxylic acid cycle (TCA), the maintenance of iron homeostasis, oxidative stress defense and the integrity of mitochondrial DNA (mtDNA). Mutations in the ACO2 gene were identified in patients suffering from a broad range of symptoms, including optic nerve atrophy, cortical atrophy, cerebellar atrophy, hypotonia, seizures and intellectual disabilities. In the present study, we identified a heterozygous 51 bp deletion (c.1699_1749del51) in ACO2 in a family with autosomal dominant inherited isolated optic atrophy. A complementation assay using aco1-deficient yeast revealed a growth defect for the mutant ACO2 variant substantiating a pathogenic effect of the deletion. We used patient-derived fibroblasts to characterize cellular phenotypes and found a decrease of ACO2 protein levels, while ACO2 enzyme activity was not affected compared to two age- and gender-matched control lines. Several parameters of mitochondrial function, including mitochondrial morphology, mitochondrial membrane potential or mitochondrial superoxide production, were not changed under baseline conditions. However, basal respiration, maximal respiration, and spare respiratory capacity were reduced in mutant cells. Furthermore, we observed a reduction of mtDNA copy number and reduced mtDNA transcription levels in ACO2-mutant fibroblasts. Inducing oxidative stress led to an increased susceptibility for cell death in ACO2-mutant fibroblasts compared to controls. Our study reveals that a monoallelic mutation in ACO2 is sufficient to promote mitochondrial dysfunction and increased vulnerability to oxidative stress as main drivers of cell death related to optic nerve atrophy.
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spelling pubmed-75415022020-10-08 Haploinsufficiency due to a novel ACO2 deletion causes mitochondrial dysfunction in fibroblasts from a patient with dominant optic nerve atrophy Neumann, Marie Anne-Catherine Grossmann, Dajana Schimpf-Linzenbold, Simone Dayan, Dana Stingl, Katarina Ben-Menachem, Reut Pines, Ophry Massart, François Delcambre, Sylvie Ghelfi, Jenny Bohler, Jill Strom, Tim Kessel, Amit Azem, Abdussalam Schöls, Ludger Grünewald, Anne Wissinger, Bernd Krüger, Rejko Sci Rep Article ACO2 is a mitochondrial protein, which is critically involved in the function of the tricarboxylic acid cycle (TCA), the maintenance of iron homeostasis, oxidative stress defense and the integrity of mitochondrial DNA (mtDNA). Mutations in the ACO2 gene were identified in patients suffering from a broad range of symptoms, including optic nerve atrophy, cortical atrophy, cerebellar atrophy, hypotonia, seizures and intellectual disabilities. In the present study, we identified a heterozygous 51 bp deletion (c.1699_1749del51) in ACO2 in a family with autosomal dominant inherited isolated optic atrophy. A complementation assay using aco1-deficient yeast revealed a growth defect for the mutant ACO2 variant substantiating a pathogenic effect of the deletion. We used patient-derived fibroblasts to characterize cellular phenotypes and found a decrease of ACO2 protein levels, while ACO2 enzyme activity was not affected compared to two age- and gender-matched control lines. Several parameters of mitochondrial function, including mitochondrial morphology, mitochondrial membrane potential or mitochondrial superoxide production, were not changed under baseline conditions. However, basal respiration, maximal respiration, and spare respiratory capacity were reduced in mutant cells. Furthermore, we observed a reduction of mtDNA copy number and reduced mtDNA transcription levels in ACO2-mutant fibroblasts. Inducing oxidative stress led to an increased susceptibility for cell death in ACO2-mutant fibroblasts compared to controls. Our study reveals that a monoallelic mutation in ACO2 is sufficient to promote mitochondrial dysfunction and increased vulnerability to oxidative stress as main drivers of cell death related to optic nerve atrophy. Nature Publishing Group UK 2020-10-07 /pmc/articles/PMC7541502/ /pubmed/33028849 http://dx.doi.org/10.1038/s41598-020-73557-4 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Neumann, Marie Anne-Catherine
Grossmann, Dajana
Schimpf-Linzenbold, Simone
Dayan, Dana
Stingl, Katarina
Ben-Menachem, Reut
Pines, Ophry
Massart, François
Delcambre, Sylvie
Ghelfi, Jenny
Bohler, Jill
Strom, Tim
Kessel, Amit
Azem, Abdussalam
Schöls, Ludger
Grünewald, Anne
Wissinger, Bernd
Krüger, Rejko
Haploinsufficiency due to a novel ACO2 deletion causes mitochondrial dysfunction in fibroblasts from a patient with dominant optic nerve atrophy
title Haploinsufficiency due to a novel ACO2 deletion causes mitochondrial dysfunction in fibroblasts from a patient with dominant optic nerve atrophy
title_full Haploinsufficiency due to a novel ACO2 deletion causes mitochondrial dysfunction in fibroblasts from a patient with dominant optic nerve atrophy
title_fullStr Haploinsufficiency due to a novel ACO2 deletion causes mitochondrial dysfunction in fibroblasts from a patient with dominant optic nerve atrophy
title_full_unstemmed Haploinsufficiency due to a novel ACO2 deletion causes mitochondrial dysfunction in fibroblasts from a patient with dominant optic nerve atrophy
title_short Haploinsufficiency due to a novel ACO2 deletion causes mitochondrial dysfunction in fibroblasts from a patient with dominant optic nerve atrophy
title_sort haploinsufficiency due to a novel aco2 deletion causes mitochondrial dysfunction in fibroblasts from a patient with dominant optic nerve atrophy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541502/
https://www.ncbi.nlm.nih.gov/pubmed/33028849
http://dx.doi.org/10.1038/s41598-020-73557-4
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