Romero July Carolina, Tonapi Sonal S, Parihar Manish, Loranc Eva, Miller Henry E, Lawrence Liesl A, Bassani Nicklas, Robledo Daniel G, Cao Lin, Nie Jia, Kanda Kairi, Stoja Aiola, Garcia Natalia, Gorthi Aparna, Stoveken Brian J, Fan Teresa W-M, Cassel Teresa A, Zha Shan, Lechleiter James D, Musi Nicolas, Dong Lily Q, Lane Andrew N, Bishop Alexander J R
Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX, USA.
Greehey Children's Cancer Research Institute, UT Health San Antonio, San Antonio, TX, USA.
Nat Commun. 2025 Jun 2;16(1):5109. doi: 10.1038/s41467-025-60304-4.
Ataxia-telangiectasia is a rare genetic disorder characterized by neurological defects, immunodeficiency, cancer predisposition, radiosensitivity, decreased blood vessel integrity, and diabetes. ATM, the protein mutated in Ataxia-telangiectasia, responds to DNA damage and oxidative stress, but its functional relationship to the progressive clinical manifestation of this disorder is not understood. CD98HC chaperones cystine/glutamate and cationic/neutral amino acid antiporters to the cell membrane, and CD98HC phosphorylation by ATM accelerates membrane localization to acutely increase amino acid transport. Loss of ATM impacts tissues reliant on heterodimeric amino acid transporters relevant to Ataxia-telangiectasia phenotypes, such as endothelial cells (telangiectasia) and pancreatic α-cells (fatty liver and diabetes), with toxic glutamate accumulation. Bypassing the antiporters restores intracellular metabolic balance in ATM-deficient cells and mouse models. These findings provide insight into the long-known benefits of N-acetyl cysteine in Ataxia-telangiectasia cells beyond oxidative stress through removing glutamate excess by producing glutathione.
共济失调毛细血管扩张症是一种罕见的遗传性疾病，其特征为神经缺陷、免疫缺陷、癌症易感性、放射敏感性、血管完整性降低以及糖尿病。共济失调毛细血管扩张症中发生突变的蛋白质ATM对DNA损伤和氧化应激作出反应，但其与该疾病进行性临床表现的功能关系尚不清楚。CD98HC将胱氨酸/谷氨酸和阳离子/中性氨基酸反向转运体转运至细胞膜，ATM介导的CD98HC磷酸化加速膜定位，从而急剧增加氨基酸转运。ATM的缺失会影响依赖与共济失调毛细血管扩张症表型相关的异二聚体氨基酸转运体的组织，如内皮细胞（毛细血管扩张）和胰腺α细胞（脂肪肝和糖尿病），导致有毒的谷氨酸积累。绕过反向转运体可恢复ATM缺陷细胞和小鼠模型中的细胞内代谢平衡。这些发现揭示了长期以来已知的N-乙酰半胱氨酸对共济失调毛细血管扩张症细胞有益的原因，即通过产生谷胱甘肽清除过量谷氨酸，而不仅仅是通过氧化应激发挥作用。
