TY - JOUR
T1 - Loss of CD98HC phosphorylation by ATM impairs antiporter trafficking and drives glutamate toxicity in Ataxia telangiectasia
AU - Romero, July Carolina
AU - Tonapi, Sonal S.
AU - Parihar, Manish
AU - Loranc, Eva
AU - Miller, Henry E.
AU - Lawrence, Liesl A.
AU - Bassani, Nicklas
AU - Robledo, Daniel G.
AU - Cao, Lin
AU - Nie, Jia
AU - Kanda, Kairi
AU - Stoja, Aiola
AU - Garcia, Natalia
AU - Gorthi, Aparna
AU - Stoveken, Brian J.
AU - Fan, Teresa W.M.
AU - Cassel, Teresa A.
AU - Zha, Shan
AU - Lechleiter, James D.
AU - Musi, Nicolas
AU - Dong, Lily Q.
AU - Lane, Andrew N.
AU - Bishop, Alexander J.R.
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025/12
Y1 - 2025/12
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/105007101063
UR - https://www.scopus.com/pages/publications/105007101063#tab=citedBy
U2 - 10.1038/s41467-025-60304-4
DO - 10.1038/s41467-025-60304-4
M3 - Article
C2 - 40456742
AN - SCOPUS:105007101063
SN - 2041-1723
VL - 16
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 5109
ER -