Novel cellular models of SLC25A38-related congenital sideroblastic anemia shed light on mitochondrial physiology and pave the way for therapeutic strategies

Congenital sideroblastic anemia (CSA) is a heterogeneous group of inherited disorders of erythropoiesis characterized by iron overload in the mitochondria of developing erythroblasts. Mutations in the mitochondrial glycine carrier, encoded by SLC25A38, cause the most common recessive form of CSA. Unfortunately, our understanding of its pathogenic mechanisms is limited, and pharmacological studies have been hindered by the lack of suitable biological models. To overcome these limitations, we generated two different cell models: K562 erythroleukemia cells with reduced SLC25A38 expression, and a lymphoblastoid cell line derived from a CSA patient with a nonsense mutation in the SLC25A38 gene. Both cell lines recapitulated the main features associated with this rare anemia, including reduced heme content and respiratory defect. However, other features were exclusively observed in the K562 mutant cells, such as an increase in mitochondrial iron and high ROS levels indicating that altered iron homeostasis and oxidative stress are secondary to heme reduction and occur erratically in different cells. Furthermore, we found that externally added pyridoxal 5'- phosphate, but not the B6 vitamers pyridoxine, pyridoxal, and pyridoxamine, rescues the altered parameters of both CSA models via a mechanism that is independent of the intracellular PLP content. Beside shedding light on the interrelation between heme biosynthesis and mitochondrial iron homeostasis, our results pave the way to new potential therapeutic strategies.