mTORC1 to AMPK switching underlies ß-cell metabolic plasticity during maturation and diabetes.

Pancreatic beta cells (ß-cells) differentiate during fetal life, but only postnatally acquire the capacity for glucose-stimulated insulin secretion (GSIS). How this happens is not clear. In exploring what molecular mechanisms drive the maturation of ß-cell function, we found that the control of cellular signaling in ß-cells fundamentally switched from the nutrient sensor target of rapamycin (mTORC1) to the energy sensor 5'-adenosine monophosphate-activated protein kinase (AMPK), and that this was critical for functional maturation. Moreover, AMPK was activated by the dietary transition taking place during weaning, and this in turn inhibited mTORC1 activity to drive the adult ß-cell phenotype. While forcing constitutive mTORC1 signaling in adult ß-cells relegated them to a functionally immature phenotype with characteristic transcriptional and metabolic profiles, engineering the switch from mTORC1 to AMPK signaling was sufficient to promote ß-cell mitochondrial biogenesis, a shift to oxidative metabolism, and functional maturation. We also found that type 2 diabetes, a condition marked by both mitochondrial degeneration and dysregulated GSIS, was associated with a remarkable reversion of the normal AMPK-dependent adult ß-cell signature to a more neonatal one characterized by mTORC1 activation. Manipulating the way in which cellular nutrient signaling pathways regulate ß-cell metabolism may thus offer new targets to improve ß-cell function in diabetes.

Deletion of a subgroup of ribosome-related genes minimizes hypoxia-induced changes and confers hypoxia tolerance.

Hypoxia is a widely occurring condition experienced by diverse organisms under numerous physiological and disease conditions. To probe the molecular mechanisms underlying hypoxia responses and tolerance, we performed a genome-wide screen to identify mutants with enhanced hypoxia tolerance in the model eukaryote, the yeast Saccharomyces cerevisiae. Yeast provides an excellent model for genomic and proteomic studies of hypoxia. We identified five genes whose deletion significantly enhanced hypoxia tolerance. They are RAI1, NSR1, BUD21, RPL20A, and RSM22, all of which encode functions involved in ribosome biogenesis. Further analysis of the deletion mutants showed that they minimized hypoxia-induced changes in polyribosome profiles and protein synthesis. Strikingly, proteomic analysis by using the iTRAQ profiling technology showed that a substantially fewer number of proteins were changed in response to hypoxia in the deletion mutants, compared with the parent strain. Computational analysis of the iTRAQ data indicated that the activities of a group of regulators were regulated by hypoxia in the wild-type parent cells, but such regulation appeared to be diminished in the deletion strains. These results show that the deletion of one of the genes involved in ribosome biogenesis leads to the reversal of hypoxia-induced changes in gene expression and related regulators. They suggest that modifying ribosomal function is an effective mechanism to minimize hypoxia-induced specific protein changes and to confer hypoxia tolerance. These results may have broad implications in understanding hypoxia responses and tolerance in diverse eukaryotes ranging from yeast to humans.