Bishop Alexander, Romero July Carolina, Tonapi Sonal, Parihar Manish, Loranc Eva, Miller Henry, Lawrence Liesl, Bassani Nicklas, Robledo Daniel, Cao Lin, Nie Jia, Kanda Kairi, Stoja Aiola, Garcia Natalia, Gorthi Aparna, Stoveken Brian, Lane Andrew, Fan Teresa, Cassel Teresa, Zha Shan, Musi Nicolas
University of Texas Health at San Antonio.
University of Kentucky College of Medicine.
Res Sq. 2024 Sep 5:rs.3.rs-4947457. doi: 10.21203/rs.3.rs-4947457/v1.
Ataxia telangiectasia (A-T) is a rare genetic disorder characterized by neurological defects, immunodeficiency, cancer predisposition, radiosensitivity, decreased blood vessel integrity, and diabetes. ATM, the protein mutated in A-T, responds to DNA damage and oxidative stress, but its functional relationship to the progressive clinical manifestation of A-T is not understood. CD98HC chaperones cystine/glutamate (x ) and cationic/neutral amino acid (yL) 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 SLC family antiporters relevant to A-T 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 both in ATM-deficient cells and mouse models. These findings provide new insight into the long-known benefits of N-acetyl cysteine to A-T cells beyond oxidative stress through removing excess glutamate by production of glutathione.
共济失调毛细血管扩张症（A-T）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、血管完整性降低和糖尿病。ATM是A-T中发生突变的蛋白质，可对DNA损伤和氧化应激作出反应，但其与A-T进行性临床表现的功能关系尚不清楚。CD98重链将胱氨酸/谷氨酸（xCT）和阳离子/中性氨基酸（y+L）反向转运体转运至细胞膜，ATM介导的CD98重链磷酸化加速膜定位，从而急剧增加氨基酸转运。ATM的缺失会影响依赖与A-T表型相关的SLC家族反向转运体的组织，如内皮细胞（毛细血管扩张）和胰腺α细胞（脂肪肝和糖尿病），这些细胞会积累有毒的谷氨酸。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。这些发现为长期以来已知的N-乙酰半胱氨酸对A-T细胞的益处提供了新的见解，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。
