PuSH - Publication Server of Helmholtz Zentrum München

Export: TXT Text RIS Endnote (RIS) BIB BibTeX
Neumann, M.A.C.* ; Grossmann, D.* ; Schimpf-Linzenbold, S.* ; Dayan, D.* ; Stingl, K.* ; Ben-Menachem, R.* ; Pines, O.* ; Massart, F.* ; Delcambre, S.* ; Ghelfi, J.* ; Bohler, J.* ; Strom, T.M. ; Kessel, A.* ; Azem, A.* ; Schöls, L.* ; Grünewald, A.* ; Wissinger, B.* ; Krüger, R.*

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

Sci. Rep. 10:16736 (2020)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.
Impact Factor
Scopus SNIP
Altmetric
3.998
1.365
Tags
Annotations
Special Publikation
Hide on homepage

Edit extra information
Edit own tags
Private
Edit own annotation
Private
Hide on publication lists
on hompage
Mark as special
publikation
Publication type Article: Journal article
Document type Scientific Article
Keywords Iron-sulfur Cluster; Metabolic-regulation; Oxidative Damage; Opa1 Isoforms; Dna Depletion; Aconitase; Protein; Neuropathy; Mutations; Alignment
Language english
Publication Year 2020
HGF-reported in Year 2020
ISSN (print) / ISBN 2045-2322
e-ISSN 2045-2322
Journal Scientific Reports
Quellenangaben Volume: 10, Issue: 1, Pages: , Article Number: 16736 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed
Institute(s) Institute of Human Genetics (IHG)
POF-Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-500700-001
Grants Israel Science Foundation
FNR within the ATTRACT program
German Research Council as part of a joint research project "TreatOPON"
Federal Ministry for Education and Research (BMBF)
European Union's (EU) Horizon2020 research and innovation program (WIDESPREAD; CENTRE-PD)
German Research Council
Fonds National de la Recherche de Luxembourg (FNR; NCER-PD)
Fonds National de la Recherche de Luxembourg (FNR; PEARL )
DOI 10.1038/s41598-020-73557-4
WOS ID WOS:000577452400005
Scopus ID 85092175067
PubMed ID 33028849
Erfassungsdatum 2020-11-16
[➜Report correction]