Santo-Domingo, JaimeLassueur, SteveGalindo, Antonio NunezAlvarez-Illera, PilarRomero-Sanz, SilviaCaldero-Escudero, Elenade la Fuente, SergioDayon, LoicWiederkehr, Andreas2023-06-192023-06-192023-06-192023-04-0110.1242/jcs.260049https://infoscience.epfl.ch/handle/20.500.14299/198430WOS:000992321600007Glucose sensing in pancreatic D-cells depends on oxidative phosphorylation and mitochondria-derived signals that promote insulin secretion. Using mass spectrometry-based phosphoproteo-mics to search for downstream effectors of glucose-dependent signal transduction in INS-1E insulinoma cells, we identified the outer mitochondrial membrane protein SLC25A46. Under resting glucose concentrations, SLC25A46 was phosphorylated on a pair of threonine residues (T44/T45) and was dephosphorylated in response to glucose-induced Ca2+ signals. Overexpression of SLC25A46 in INS-1E cells caused complete mitochondrial fragmentation, resulting in a mild mitochondrial defect associated with lowered glucose-induced insulin secretion. In contrast, inactivation of the Slc25a46 gene resulted in dramatic mitochondrial hyperfusion, without affecting respiratory activity or insulin secretion. Consequently, SLC25A46 is not essential for metabolism-secretion coupling under normal nutrient conditions. Importantly, insulin-secreting cells lacking SLC25A46 had an exacerbated sensitivity to lipotoxic conditions, undergoing massive apoptosis when exposed to palmitate. Therefore, in addition to its role in mitochondrial dynamics, SLC25A46 plays a role in preventing mitochondria-induced apoptosis in INS-E cells exposed to nutrient stress. By protecting mitochondria, SLC25A46 might help to maintain D-cell mass essential for blood glucose control.Cell Biologymitochondriabeta-cellmitochondrial dynamicsphosphorylationlipotoxicitypancreatic beta-cellislet cellsfatty-acidsglucosemetabolismopa1calciumcristaedrp1transportertext::journal::journal article::research article