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.
Bibliographical noteFunding Information:
We gratefully acknowledge the prior work of Beate Leo-Kottler to study inherited optic neuropathies. RK was supported by the Fonds National de la Recherche de Luxembourg (FNR; PEARL [FNR/P13/6682797/Krüger] and NCER-PD), the German Research Council (KR2119/8-1), the European Union’s (EU) Horizon2020 research and innovation program (WIDESPREAD; CENTRE-PD; grant agreement No. 692320), and the Federal Ministry for Education and Research (BMBF; Mito-PD 031A 430 A). Supported by funds of the German Research Council (Wi1189/11-1) as part of a joint research project "TreatOPON" within the framework of the ERA-NET E-Rare 3 call to B.W. AG acknowledges support from the FNR within the ATTRACT program (Model IPD, FNR9631103). A.A. and O.O. were supported by the Israel Science Foundation.
© 2020, The Author(s).