Glucose sensing in pancreatic beta-cells depends on oxidative phosphorylation and mitochondria-derived signals that promote insulin secretion. Using mass spectrometry-based phosphoproteomics to search for down-stream 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 calcium 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 but 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 may help to maintain beta-cell mass essential for blood glucose control.
SLC25A46 promotes mitochondrial fission and mediates resistance to lipotoxic stress in INS-1E insulin secreting cells
- Award Group:
- Funder(s): Fondation Nestle
- Award Id(s): No number
- Funder(s):
- Award Group:
- Funder(s): Junta de castilla y Leon
- Award Id(s): CCVC8485
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Jaime Santo-Domingo, Steve Lassueur, Antonio Núñez Galindo, Pilar Alvarez-Illera, Silvia Romero-Sanz, Elena Caldero-Escudero, Sergio de la Fuente, Loïc Dayon, Andreas Wiederkehr; SLC25A46 promotes mitochondrial fission and mediates resistance to lipotoxic stress in INS-1E insulin secreting cells. J Cell Sci 2023; jcs.260049. doi: https://doi.org/10.1242/jcs.260049
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