Pancreatic beta-cells are central regulators of glucose homeostasis. By tightly coupling nutrient sensing and granule exocytosis, beta-cells adjust the secretion of insulin to the circulating blood gl Show more
Pancreatic beta-cells are central regulators of glucose homeostasis. By tightly coupling nutrient sensing and granule exocytosis, beta-cells adjust the secretion of insulin to the circulating blood glucose levels. Failure of beta-cells to augment insulin secretion in insulin-resistant individuals leads progressively to impaired glucose tolerance, Type 2 diabetes, and diabetes-related diseases. Mitochondria play a crucial role in β-cells during nutrient stimulation, linking the metabolism of glucose and other secretagogues to the generation of signals that promote insulin secretion. Mitochondria are double-membrane organelles containing numerous channels allowing the transport of ions across both membranes. These channels regulate mitochondrial energy production, signalling, and cell death. The mitochondria of β-cells express ion channels whose physio/pathological role is underappreciated. Here, we describe the mitochondrial ion channels identified in pancreatic β-cells, we further discuss the possibility of targeting specific β-cell mitochondrial channels for the treatment of Type 2 diabetes, and we finally highlight the evidence from clinical studies. LINKED ARTICLES: This article is part of a themed issue on Cellular metabolism and diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.10/issuetoc. Show less
Mitochondria take up Ca 2+ through the mitochondrial calcium uniporter complex to regulate energy production, cytosolic Ca 2+ signaling, and cell death 1 , 2 . In mammals, the uniporter complex (u Show more
Mitochondria take up Ca 2+ through the mitochondrial calcium uniporter complex to regulate energy production, cytosolic Ca 2+ signaling, and cell death 1 , 2 . In mammals, the uniporter complex (uniplex) contains four core components: the pore-forming MCU, gatekeeper MICU1 and MICU2, and an auxiliary EMRE subunit essential for Ca 2+ transport 3 â 8 . To prevent detrimental Ca 2+ overload, the activity of MCU must be tightly regulated by MICUs, which sense the changes in cytosolic Ca 2+ concentrations to switch MCU on and off 9 , 10 . Here, we report cryo-EM structures of human mitochondrial calcium uniporter holocomplex in inhibited and Ca 2+ -activated states. These structures define the architecture of this multi-component Ca 2+ uptake machinery and reveal the gating mechanism by which MICUs control uniporter activity. This work provides a framework for understanding regulated Ca 2+ uptake in mitochondria and lends clues to modulate uniporter activity for treating mitochondrial Ca 2+ overload-related diseases. Show less
Abstract TFIIH is a 10âsubunit complex that regulates RNA polymerase II (pol II) transcription but also serves other important biological roles. Although much remains unknown about TFIIH function in Show more
Abstract TFIIH is a 10âsubunit complex that regulates RNA polymerase II (pol II) transcription but also serves other important biological roles. Although much remains unknown about TFIIH function in eukaryotic cells, much progress has been made even in just the past few years, due in part to technological advances (e.g. cryoEM and single molecule methods) and the development of chemical inhibitors of TFIIH enzymes. This review focuses on the major cellular roles for TFIIH, with an emphasis on TFIIH function as a regulator of pol II transcription. We describe the structure of TFIIH and its roles in pol II initiation, promoterâproximal pausing, elongation, and termination. We also discuss cellular roles for TFIIH beyond transcription (e.g. DNA repair, cell cycle regulation) and summarize small molecule inhibitors of TFIIH and diseases associated with defects in TFIIH structure and function. Show less