Neumann2020 - Haploinsufficiency due to a novel ACO2 deletion causes mitochondrial dysfunction in fribroblasts from a patient with dominant optic nerve atrophy.pdf
[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.
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