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

Authors

Marie Anne-Catherine Neumann ^{1 2}, Dajana Grossmann ³, Simone Schimpf-Linzenbold ^{4 5}, Dana Dayan ⁶, Katarina Stingl ⁷, Reut Ben-Menachem ⁸, Ophry Pines ^{8 9}, François Massart ¹, Sylvie Delcambre ¹, Jenny Ghelfi ¹, Jill Bohler ¹, Tim Strom ¹⁰, Amit Kessel ⁶, Abdussalam Azem ⁶, Ludger Schöls ^{11 12}, Anne Grünewald ^{1 13}, Bernd Wissinger ^{5 7}, Rejko Krüger ^{14 15 16}

Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg.
Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg. dajana.grossmann@med.uni-rostock.de.
CeGaT GmbH and Praxis für Humangenetik Tübingen, Tübingen, Germany.
Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tuebingen, Tübingen, Germany.
School of Neurobiology, Biochemistry and Biophysics, George S Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
Centre for Ophthalmology, University Eye Hospital, University of Tübingen, Tübingen, Germany.
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.
Institute of Human Genetics, Helmholtz Zentrum Muenchen, Neuherberg, Germany.
Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg. rejko.krueger@uni.lu.
Transversal Translational Medicine, Luxembourg Institute of Health (LIH), Strassen, Luxembourg. rejko.krueger@uni.lu.
Parkinson Research Clinic, Centre Hospitalier de Luxembourg (CHL), Luxembourg, Luxembourg. rejko.krueger@uni.lu.

Abstract

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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