| Reference : Haploinsufficiency due to a novel ACO2 deletion causes mitochondrial dysfunction in f... |
| Scientific journals : Article | |||
| Life sciences : Biochemistry, biophysics & molecular biology | |||
| Systems Biomedicine | |||
| http://hdl.handle.net/10993/44703 | |||
| Haploinsufficiency due to a novel ACO2 deletion causes mitochondrial dysfunction in fibroblasts from a patient with dominant optic nerve atrophy | |
| English | |
Neumann, Marie Anne-Catherine*  [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >] | |
| Grossmann, Dajana* [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >] | |
| Schimpf-Linzenbold, Simone [CeGaT GmbH and Praxis für Humangenetik Tübingen, Tübingen, Germany > > > ; Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tuebingen, Tübingen, Germany] | |
| Dayan, Dana [School of Neurobiology, Biochemistry and Biophysics, George S Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel] | |
| Stingl, Katarina [Centre for Ophthalmology, University Eye Hospital, University of Tübingen, Tübingen, Germany] | |
| Ben-Menachem, Reut [Department of Microbiology and Molecular Genetics, IMRIC, Faculty of Medicine, Hebrew University, Jerusalem, Israel] | |
| Pines, Ophry [Department of Microbiology and Molecular Genetics, IMRIC, Faculty of Medicine, Hebrew University, Jerusalem, Israel > > > ; NUS-HUJ-CREATE Program and the Department of Microbiology, School of Medicine, National University of Singapore, Singapore, Singapore] | |
| Massart, François [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience >] | |
| Delcambre, Sylvie [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Molecular and Functional Neurobiology >] | |
| Ghelfi, Jenny [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Molecular and Functional Neurobiology >] | |
| Bohler, Jill [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >] | |
| Strom, Tim [Institute of Human Genetics, Helmholtz Zentrum Muenchen, Neuherberg, Germany] | |
| Kessel, Amit [School of Neurobiology, Biochemistry and Biophysics, George S Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel] | |
| Azem, Abdussalam [School of Neurobiology, Biochemistry and Biophysics, George S Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel] | |
| Schöls, Ludger [Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany > > > ; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany] | |
| Grünewald, Anne [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Molecular and Functional Neurobiology >] | |
| Wissinger, Bernd [Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tuebingen, Tübingen, Germany > > > ; Centre for Ophthalmology, University Eye Hospital, University of Tübingen, Tübingen, Germany] | |
| Krüger, Rejko [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience >] | |
| * These authors have contributed equally to this work. | |
| 7-Oct-2020 | |
| Scientific Reports | |
| Nature Publishing Group | |
| Yes (verified by ORBilu) | |
| International | |
| 2045-2322 | |
| London | |
| United Kingdom | |
| [en] 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. | |
| http://hdl.handle.net/10993/44703 | |
| 10.1038/s41598-020-73557-4 | |
| H2020 ; 692320 - CENTRE-PD - TWINNING for a Comprehensive Clinical Centre for the Diagnosis and Treatment of Parkinson's Disease | |
| FnR ; FNR6682797 > Rejko Krüger > Endophenotypes in Neurodegeneration > Comprehensive assessment of endophenotypes in neurodegenerative diseases - translating impaired molecular signalling pathways into novel therapeutic strategies for Parkinson’s disease > 01/06/2014 > 31/05/2019 > 2013 |
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