Bcl-xL restricts transcriptional, morphological and functional decompensation of β-cell mitochondria under chronic glucose excess

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-xL 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 Ca2+ signaling and insulin secretion. Deletion of Bcl-xL 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-xL-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-xL limits high glucose-induced mitochondrial ROS (mitoROS) levels and pharmacological normalization of mitoROS in Bcl-xL 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-xL as an important safeguard against transcriptional and functional decompensation of β-cell mitochondria. Bcl-xL and mitoROS may thus be viable targets to prevent early β-cell dysfunction and the progression of diabetes. ### Competing Interest Statement The authors have declared no competing interest.