4.5 Article

SLC25A46 promotes mitochondrial fission and mediates resistance to lipotoxic stress in INS-1E insulin-secreting cells

Journal

JOURNAL OF CELL SCIENCE
Volume 136, Issue 8, Pages -

Publisher

COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.260049

Keywords

Mitochondria; beta-cell; Mitochondrial dynamics; Phosphorylation; Lipotoxicity

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Glucose sensing in pancreatic D-cells relies on mitochondrial signals and oxidative phosphorylation to promote insulin secretion. SLC25A46, an outer mitochondrial membrane protein, was identified as a downstream effector of glucose-dependent signal transduction. It plays a role in mitochondrial dynamics and protects mitochondria from apoptosis under nutrient stress in INS-E cells.
Glucose 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.

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