Chvanov, Michael, Voronina, Svetlana, Zhang, Xiaoying, Telnova, Svetlana, Chard, Robert, Ouyang, Yulin, Armstrong, Jane, Tanton, Helen, Awais, Muhammad, Latawiec, Diane et al (show 3 more authors)
(2020)
Knockout of the Mitochondrial Calcium Uniporter Strongly Suppresses Stimulus-Metabolism Coupling in Pancreatic Acinar Cells but Does not Reduce Severity of Experimental Acute Pancreatitis.
CELLS, 9 (6).
E1407-.
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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 Ca<sup>2+</sup> increases in the cytosol and mitochondria of pancreatic acinar cells. The mitochondrial calcium uniporter (MCU) mediates mitochondrial Ca<sup>2+</sup> uptake that regulates bioenergetics and plays an important role in cell survival, damage and death. Aberrant Ca<sup>2+</sup> 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<sup>-/-</sup> mice display dramatically reduced mitochondrial Ca<sup>2+</sup> uptake. This is consistent with the drastic changes of stimulus-metabolism coupling, manifested by the reduction of mitochondrial NADH/FAD<sup>+</sup> 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | acute pancreatitis, Ca(2+)signaling, mitochondrial calcium uniporter, pancreatic acinar cells |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 23 Jun 2020 08:03 |
| Last Modified: | 08 Feb 2024 11:27 |
| DOI: | 10.3390/cells9061407 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3091381 |
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