Santoro Antonella, De Santis Silvia, Palmieri Ferdinando, Vozza Angelo, Agrimi Gennaro, Andolfo Immacolata, Russo Roberta, Palazzo Antonio, Storlazzi Clelia Tiziana, Ferrucci Arianna, Jun Yong Woong, Kool Eric T, Fiermonte Giuseppe, Iolascon Achille, Paradies Eleonora, Marobbio Carlo Marya Thomas, Palmieri Luigi
Department of Biosciences, Biotechnology and Environment, University of Bari Aldo Moro, 70125 Bari, Italy.
CNR Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IBIOM), 70126 Bari, Italy.
Int J Mol Sci. 2024 Dec 12;25(24):13314. doi: 10.3390/ijms252413314.
Mutations in the SLC25A38 gene are responsible for the second most common form of congenital sideroblastic anemia (CSA), a severe condition for which no effective treatment exists. We developed and characterized a K562 erythroleukemia cell line with markedly reduced expression of the SLC25A38 protein (A38-low cells). This model successfully recapitulated the main features of CSA, including reduced heme content and mitochondrial respiration, increase in mitochondrial iron, ROS levels and sensitivity to oxidative stress. Notably, our study uncovered a new role for extracellular pyridoxal 5'-phosphate (PLP) and other P2 receptor antagonists in rescuing the altered parameters of A38-low cells (for example, the heme content of the A38-low cells was increased from about 50% to about 80% by the P2 receptor antagonists treatment compared with the value of the controls). These findings suggest that targeting P2 receptors could represent a promising therapeutic approach for SLC25A38-associated CSA.
SLC25A38基因突变是导致先天性铁粒幼细胞贫血（CSA）第二常见形式的原因，CSA是一种严重疾病，目前尚无有效治疗方法。我们开发并鉴定了一种K562红白血病细胞系，其SLC25A38蛋白表达明显降低（A38低表达细胞）。该模型成功重现了CSA的主要特征，包括血红素含量降低和线粒体呼吸作用减弱、线粒体铁增加、活性氧水平升高以及对氧化应激的敏感性增加。值得注意的是，我们的研究发现细胞外磷酸吡哆醛（PLP）和其他P2受体拮抗剂在挽救A38低表达细胞的改变参数方面具有新作用（例如，与对照组相比，P2受体拮抗剂处理后A38低表达细胞的血红素含量从约50%增加到约80%）。这些发现表明，靶向P2受体可能是治疗SLC25A38相关CSA的一种有前景的治疗方法。
