Objective: To investigate the pathogenic effect of single heterozygous mutations in ATP13A2, we determined the function and morphological changes of mitochondria in skin fibroblasts derived from single heterozygous ATP13A2 mutation carriers and healthy controls.

Background: Homozygous and compound heterozygous mutations in ATP13A2 have been invariably associated with Kufor-Rakeb syndrome, an autosomal recessive juvenile-onset parkinsonism. Interestingly, several studies have reported the development of Parkinson’s disease (PD) in single heterozygous ATP13A2 mutation carriers, suggesting their role as a risk factor for PD. However, the pathogenicity of these single mutations remained unexplored.

Methods: We determined the extent of mitochondrial dysfunction in skin fibroblast lines derived from three single heterozygous ATP13A2 mutation carriers (sHTZ-PK9; one carrier carrying c.3176T>G and two with c.3057delC) and healthy controls (n=3). In addition, we also assessed possible alterations in Zn²⁺ metabolism.

Results: The level of total ATP13A2 transcripts was lower in the cells carrying c.3057delC in ATP13A2 compared to controls, while it was higher in the cells carrying c.3176T>G with both wild-type and mutant transcripts elevated to a similar level. When mitochondrial respiration was assessed, sHTZ-PK9 fibroblasts showed a significant decrease in the maximal oxygen consumption rate. Furthermore, ATP production rate and mitochondrial membrane potential, as well as mitochondrial network interconnectivity were also reduced in the sHTZ-PK9 cells, indicating mitochondrial dysfunction. However, the level of reactive oxygen species remained unchanged. In addition, sHTZ-PK9 cells showed decreased expression of zinc transporters and increased cytotoxicity to ZnCl₂ treatment, suggesting impaired Zn²⁺ homeostasis, while the intracellular free Zn²⁺ levels were similar between the control and sHTZ-PK9 cells.

Conclusions: Our results indicate a mild degree of mitochondrial dysfunction in fibroblasts carrying single heterozygous ATP13A2 mutations despite a differential effect of the mutations on ATP13A2 expression. Given that impaired Zn²⁺ homeostasis is detected in sHTZ-PK9 cells, it is possible that altered Zn²⁺ metabolism underlies mitochondrial dysfunction. Collectively, these findings demonstrate that single heterozygous ATP13A2 mutations may function as a risk factor for PD by impairing cellular bioenergetics.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/mitochondrial-dysfunction-in-skin-fibroblasts-from-single-heterozygous-atp13a2-park9-mutation-carriers/