RT info:eu-repo/semantics/article
T1 SLC25A46 promotes mitochondrial fission and mediates resistance to lipotoxic stress in INS-1E insulin-secreting cells
A1 Santo-Domingo, Jaime
A1 Lassueur, Steve
A1 Galindo, Antonio Núñez
A1 Alvarez-Illera, Pilar
A1 Romero-Sanz, Silvia
A1 Caldero-Escudero, Elena
A1 de la Fuente, Sergio
A1 Dayon, Loïc
A1 Wiederkehr, Andreas
AB Glucose sensing in pancreatic β-cells depends on oxidative phosphorylation and mitochondria-derived signals that promote insulin secretion. Using mass spectrometry-based phosphoproteomics 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 β-cell mass essential for blood glucose control.
SN 0021-9533
YR 2023
FD 2023
LK https://uvadoc.uva.es/handle/10324/73918
UL https://uvadoc.uva.es/handle/10324/73918
LA eng
NO Santo-Domingo J, Lassueur S, Galindo AN, Alvarez-Illera P, Romero-Sanz S, Caldero-Escudero E, de la Fuente S, Dayon L, Wiederkehr A. SLC25A46 promotes mitochondrial fission and mediates resistance to lipotoxic stress in INS-1E insulin-secreting cells. J Cell Sci. 2023 Apr 15;136(8):jcs260049. doi: 10.1242/jcs.260049. Epub 2023 Apr 14. PMID: 36942724.
DS UVaDOC
RD 22-ene-2025