SLC25A12-mediated glutamate translocation contributes to NaAsO₂-induced ferroptosis and islet β-cell dysfunction

The mechanism for induction of ferroptosis and islet β-cell dysfunction following arsenic exposure remains elusive. Solute carrier family 25 member 12 (SLC25A12) is a component of the malate-aspartate shuttle and is essential for insulin secretion. However, the role of SLC25A12 in arsenic-induced ferroptosis and islet β-cell dysfunction is unknown. Because ferroptosis is involved in pancreatic dysfunction through mitochondrial reactive oxygen species (MtROS), the present study sought to elucidate the explicit mechanism of MtROS generation in arsenic-induced ferroptosis and pancreatic dysfunction. SLC25A12 was identified as a key mediator of arsenic-induced islet β-cell dysfunction and ferroptosis. Mechanistically, SLC25A12 suppression inhibited glutamate transport from the cytoplasm to mitochondria and decreased MtROS levels by alleviating mitochondrial dysfunction. Thus, SLC25A12-mediated glutamate translocation and MtROS generation contributed to NaAsO₂-triggered islet β-cell dysfunction and ferroptosis. These results provided new clues for the SLC25A12 potential as a therapeutic target for diabetes.