A unique pancreatic mitochondrial response to calcium and its role in apoptosis

The exocrine pancreas synthesises more protein per gram of tissue than any other mammalian organ (with the exception of the lactating breast) and produces 6–20 g of digestive enzyme per day. This enormous metabolic activity requires an equally high energy supply for protein synthesis, transport and storage, as well as regulated secretion of active digestive enzymes and protease zymogens. Pancreatic acinar cells have therefore a high rate of mitochondrial energy metabolism. Pancreatic mitochondria effectively use nicotine adenine dinucleotide (NAD⁺)-dependent substrates to maintain the mitochondrial membrane potential (Δψm). Energy stored as Δψm is mainly used for two energy-requiring processes: ATP synthesis and Ca²⁺ accumulation. ATP is further needed for protein synthesis, signal transduction, intracellular ion homeostasis, vesicular transport to the apical pole of the acinar cell, and exocytosis of digestive enzymes into the duct lumen.

In pancreatic acinar cells a rise in intracellular free Ca²⁺ is the key signal transduction mechanism regulating stimulus–secretion coupling. Following exposure of the cell to cholecystokinin (CCK) or other hormones Ca²⁺ is released from intracellular stores via either Inositol triphosphate (IP3), nicotinic acid adenine dinucleotide phosphate (NAADP) or cyclic ADP ribose (cADPR) signalling pathways.1 2 The endoplasmatic reticulum (ER) operates as the main Ca²⁺ storing compartment, and this organelle is mostly located in the basal portion of the cell surrounding the nucleus.3 Additional Ca²⁺ storing organelles have been identified in the apical area of acinar cells and may be composed of ER protrusions into that region.2 3 Under physiological conditions hormonal stimulation results in an oscillating wave of free Ca²⁺ that is initiated in the apical portion of acinar cells and enables exocytosis of zymogen granule content from the luminal plasma membrane. Recently, …