Mitochondrial impairment, particularly in beta cells, is closely associated with metabolic disorders such as type 2 diabetes (T2D). In a recent paper, Walker et al. demonstrate that integrated stress response (ISR) signalling from the mitochondria to the nucleus leads to dedifferentiation and loss of maturity in beta cells, causing glucose intolerance and defects in insulin secretion.

To determine the role of mitochondrial dysfunction in T2D, the authors generated beta cell-specific mouse models with abnormalities in mitochondrial quality control and observed accompanying metabolic dysfunction. Transcriptomic analysis of islets showed changes in expression of cell maturity markers, suggesting acquisition of cellular immaturity, and induction of the ISR. Single-nucleus experiments demonstrate loss of chromatin accessibility at terminal identity genes. Finally, the authors show that small-molecule inhibition of the ISR alleviates the loss of beta cell mass and glucose intolerance caused by mitochondrial impairment.