Inter-organelle crosstalk in the pancreatic β cell: Membrane contact sites as regulators of insulin secretion

Pancreatic β cells play a crucial role in glucose homeostasis by producing and secreting insulin. Impaired insulin release leads to chronic hyperglycemia and contributes to the development of type 2 diabetes (T2D). Insulin is stored in secretory granules, which are transported to the plasma membrane for exocytosis to the circulation in response to elevated blood glucose levels. The mechanisms that couple glucose metabolism to insulin secretion are complex and involve both Ca2+ and phospholipid signaling. Membrane contact sites (MCSs) are specialized regions where organelle membranes are closely apposed, providing a conduit for non-vesicular lipid exchange and Ca2+ transport between the two compartments, but their importance for normal β cell function is not known. Here, we discover a new type of MCS involving the ER and insulin granules, which facilitate lipid exchange between the two organelles. Oxysterol-binding protein (OSBP), a cytosolic lipid transport protein (LTP), was recruited to these MCSs in a Ca2+- and pH-dependent manner and catalyzed the exchange of granular PI(4)P for ER cholesterol. This mechanism was essential for normal insulin secretion. Transmembrane protein 24 (TMEM24) is an ER-anchored LTP that dynamically interacts with the plasma membrane (PM) and provides it with phosphatidylinositol, a precursor of other phosphoinositides. We found that TMEM24 localization was spatially and temporally regulated by Ca2+ and diacylglycerol (DAG), and that, upon dissociation from the PM, it stabilized at ER-mitochondria MCSs. Loss of TMEM24 led to dysregulation of both ER and mitochondria Ca2+, impaired ATP production, and reduced insulin secretion. High-resolution imaging further revealed that TMEM24 also localized close to a subset of newly synthesized insulin granules that were in proximity to mitochondria. These organelle contacts were additionally defined by the presence of voltage-dependent anion channel (VDAC) and Mitofusin-2 on the mitochondria and the vesicular nucleotide transporter (VNUT) on the insulin granules. Reduced VNUT expression abolished the interaction between mitochondria and insulin granules and led to impaired insulin granule biogenesis and exocytosis. Collectively, our findings highlight the significant roles of different MCSs in maintaining normal β cell function.