PuSH - Publikationsserver des Helmholtz Zentrums München: Haploinsufficiency due to a novel <em>ACO2</em> deletion causes mitochondrial dysfunction in fibroblasts from a patient with dominant optic nerve atrophy.

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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)

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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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