Abstract
Acute pancreatitis is a frequent disease that lacks specific drug treatment. Unravelling the molecular mechanisms of acute pancreatitis is essential for the development of new therapeutics. Several inducers of acute pancreatitis trigger sustained Ca2+ increases in the cytosol and mitochondria of pancreatic acinar cells. The mitochondrial calcium uniporter (MCU) mediates mitochondrial Ca2+ uptake that regulates bioenergetics and plays an important role in cell survival, damage and death. Aberrant Ca2+ signaling and mitochondrial damage in pancreatic acinar cells have been implicated in the initiation of acute pancreatitis. The primary aim of this study was to assess the involvement of the MCU in experimental acute pancreatitis. We found that pancreatic acinar cells from MCU−/− mice display dramatically reduced mitochondrial Ca2+ uptake. This is consistent with the drastic changes of stimulus-metabolism coupling, manifested by the reduction of mitochondrial NADH/FAD+ responses to cholecystokinin and in the decrease of cholecystokinin-stimulated oxygen consumption. However, in three experimental models of acute pancreatitis (induced by caerulein, taurolithocholic acid 3-sulfate or palmitoleic acid plus ethanol), MCU knockout failed to reduce the biochemical and histological changes characterizing the severity of local and systemic damage. A possible explanation of this surprising finding is the redundancy of damaging mechanisms activated by the inducers of acute pancreatitis.
Highlights
Acute pancreatitis (AP) is a frequent disease of considerable morbidity [1,2]
We investigated the effects of mitochondrial calcium uniporter (MCU) knockout on cytosolic and mitochondrial Ca2+ responses to known AP inducers
To monitor mitochondrial Ca2+ responses ([Ca2+ ]m), pancreatic acinar cells from MCU−/− and wild type (WT) mice were transfected with a genetically-encoded fluorescent mitochondrial calcium sensor MtRCaMP [54] (Figure 1B and Figure S1B)
Summary
Mitochondrial dysfunction has been shown to play an important role in death/damage of pancreatic acinar cell and the initiation of AP [3,4,5,6]. Entry to the severity of this pancreatic disease. The important secretagogues acetylcholine and cholecystokinin (CCK) utilize Ca2+ signaling cascade to trigger and regulate secretion of digestive. Cells 2020, 9, 1407 enzymes and precursors of digestive enzymes from pancreatic acinar cells (reviewed in [7,8,9]). Cytosolic Ca2+ signals are produced as a result of Ca2+ release from the intracellular stores (primarily the endoplasmic reticulum (ER)) and Ca2+ entry via the store-operated Ca2+ channels (SOCS) in the plasma membrane (PM) [7,8,9]. Cytosolic Ca2+ responses in the acinar cells are accompanied by Ca2+
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