PhD Scientific Days 2025

Poster Session III. - C: Molecular Medicine

Epigenetic Consequences of Impaired Ascorbate Transport in a Double Knockout Mouse Model of Arterial Tortuosity Syndrome

Name of the presenter

Veszelyi Krisztina Nóra

Institute/workplace of the presenter

Institute of Translational Medicine

Authors

Krisztina Nóra Veszelyi¹, Viola Varga¹, Csilla Emese Németh², Éva Margittai¹

1: Semmelweis University, Institute of Translational Medicine
2: Semmelweis University, Department of Molecular Biology

Text of the abstract

Introduction: Arterial Tortuosity Syndrome (ATS) is a rare autosomal recessive connective tissue disorder marked by tortuosity of large arteries and aneurysm formation. ATS is caused by loss-of-function mutations in the SLC2A10 gene encoding GLUT10, a transporter of dehydroascorbate, the oxidized form of vitamin C, across endomembranes. Recent studies show ascorbate acts as a cofactor for DNA and histone demethylases like TET enzymes, affecting epigenetic regulation. Patients with ATS have been found to exhibit abnormal epigenetic modifications. We hypothesize that impaired nuclear accumulation of ascorbate in ATS disrupts DNA and histone demethylation processes, leading to epigenetic alterations that may play a role in the pathomechanism of the disease.
Aims: We aimed to develop a double knockout (DKO) mouse model lacking GLUT10 transporter and vitamin C synthesis, to study subcellular ascorbate distribution and expression of vitamin C-dependent epigenetic enzymes.
Methods: DKO mice and wild type controls were assigned to two dietary regimens: with or without vitamin C supplementation. Vitamin C concentrations in brain, liver, and liver subcellular fractions were quantified using HPLC-UV/DAD. mRNA expression levels of TET enzymes were examined by qPCR, while TET1 protein expression was studied by Western blotting. Global DNA methylation and hydroxymethylation were analyzed by dot blot assays.
Results: Ascorbate levels were significantly reduced in DKO mice lacking dietary supplementation but were restored upon vitamin C administration. Notably, nuclear ascorbate concentrations remained lower in DKO mice compared to wild type controls, even with supplementation. TET1 mRNA and protein expression were significantly elevated in the brains of DKO mice without vitamin C, relative to wild type mice receiving vitamin C supplementation. Both global DNA methylation and DNA hydroxymethylation was significantly decreased in DKO mouse brains.
Conclusion: Our findings demonstrate that DKO mice exhibited altered ascorbate distribution and vitamin C-dependent enzyme expression, which might initiate the novel idea of considering ATS as an ascorbate compartmentalization disorder.
Funding: Supported by the EKÖP-2024-105 New National Excellence Program of the Ministry for Culture and Innovation from the source of the National Research, Development and Innovation Fund.