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• W3209952409 abstract "ABSTRACT In the progression of diabetes, pancreatic islet β-cells respond to increased metabolic demand with functional compensation, followed by pathogenic decompensation of mitochondria-dependent insulin secretion. It is not clear what mechanisms drive, or control, mitochondrial decompensation. Here, we report that anti-apoptotic Bcl-x L maintains mitochondrial integrity in β-cells under non-apoptotic levels of glucose stress. Prolonged glucose excess causes transcriptional reprogramming of glycolysis and β-cell identity genes, while sensitizing glucose-stimulated Ca 2+ signaling and insulin secretion. Deletion of Bcl-x L amplifies this insulin hypersecretion and increases mitochondrial fusion, mitochondrial volume, and oxygen consumption, whereas ATP-coupled respiration and mitochondrial hyperpolarization become impaired. Of note, Bcl-x L -deficient β-cells have impaired Pgc-1α expression, and develop specific defects in the expression of Tfam, mitochondrial ribosomal genes, and OXPHOS components under glucose stress. Bcl-x L limits high glucose-induced mitochondrial ROS (mitoROS) levels and pharmacological normalization of mitoROS in Bcl-x L KO cells rescues glucose-induced defects in mitochondrial gene expression and changes to β-cell identity. Our data identify mitoROS as a primary retrograde driver of transcriptional re-wiring in β-cells exposed to excess glucose, and reveal Bcl-x L as an important safeguard against transcriptional and functional decompensation of β-cell mitochondria. Bcl-x L and mitoROS may thus be viable targets to prevent early β-cell dysfunction and the progression of diabetes." @default.
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• W3209952409 date "2021-10-26" @default.
• W3209952409 modified "2023-09-27" @default.
• W3209952409 title "Bcl-xL restricts transcriptional, morphological and functional decompensation of β-cell mitochondria under chronic glucose excess" @default.
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• W3209952409 doi "https://doi.org/10.1101/2021.10.25.465491" @default.
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