Mitochondrial function and the regulation of the pancreatic beta-cell

Mitochondria adapt and adjust their metabolic functions to the need of the cell. Depending on the tissue mitochondria display different substrate preferences and may for example switch from glucose oxidation to mostly fatty acid oxidation and vice versa. These phenomena are controlled by cellular signaling and are essential for tissues to maintain normal function despite changing nutrient conditions. In my team, we are interested in the molecular mechanisms that allow mitochondria to sense cellular signaling and adjust their energy output accordingly.

Our focus has been the nutrient sensing pancreatic beta-cell. This highly specialized cell type adjusts release of the blood glucose lowering hormone insulin to the concentration of circulating glucose and other nutrient secretagogues. Mitochondria are essential for nutrient sensing in the beta-cell. During glucose stimulation beta-cell mitochondria accelerate their metabolism, oxygen consumptions and ATP synthesis rates. These changes occur over a time-course of several tens of seconds to up to about one hour. Increased supply of pyruvate derived from glucose explains only a smaller fraction of this substrate induced mitochondrial activation. We could show that mitochondrial calcium uptake during nutrient stimulation is required for robust mitochondrial activation and sustained insulin secretion. In addition, we demonstrated that several signaling pathways promote mitochondrial activation. We have also identified a small number of mitochondrial proteins that undergo glucose dependent phosphorylation. Such effector proteins may link beta-cell stimulation to the regulation of mitochondrial activity.

Gradual decline of beta-cell function and the inability to secrete sufficient insulin to compensate for insulin resistance result in loss of glucose control and the development of Type 2 diabetes. We propose that declining mitochondrial function is a main determinant of gradual loss of beta-cell function during aging and diabetes progression. We investigate how nutrient oversupply such as observed in individuals with Type 2 diabetes alters and eventually impairs mitochondrial function in human pancreatic beta-cells. Protecting beta-cell mitochondria is a novel approach for the maintenance of beta-cell function and the prevention of Type 2 diabetes.

Figure legend. Electron microscope image of mitochondria in a pancreatic beta-cell.

Keywords

• Pancreatic beta-cell
• Mitochondria
• Type 2 diabetes
• Metabolomics
• Calcium
• ATP