Knockout of the Mitochondrial Calcium Uniporter Strongly Suppresses Stimulus-Metabolism Coupling in Pancreatic Acinar Cells but Does Not Reduce Severity of Experimental Acute Pancreatitis

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.

Metabolic adaptation to the chronic loss of Ca2+ signaling induced by KO of IP3 receptors or the mitochondrial Ca2+ uniporter

“…Many studies have examined the physiological consequences of disrupting mitochondrial Ca 2+ signaling using global and tissue-specific MCU KO mouse models. In most cases, a relatively mild phenotype at baseline has been observed in tissues, such as the heart ( 33 ), skeletal muscle ( 34 ), exocrine pancreas ( 35 ), endocrine pancreas ( 36 ), brown adipose tissue ( 37 ), and photoreceptors ( 38 ) suggesting the existence of robust adaptive mechanisms that have yet to be fully characterized, including upregulation of alternative mechanisms of mitochondrial Ca 2+ transport. Where metabolic changes have been investigated in MCU KOs, the results have generally been tissue specific.…”

Dynamic Regulation of Mitochondrial [Ca2+] in Hippocampal Neurons

“…Rhod-2 is actually a general calcium sensor, but once it enters the cell, and excess of it is washed out, it has an apparent selectivity for [Ca 2+ ]m. In any case, Rhod-2 is a diffusible agent, and is not likely to predict the precise localization of changes in [Ca 2+ ]m. Moreover, the introduction of Rhod2 involves an injection of the agent into the cell. The genetically encoded mtRCaMP [ 11 , 25 ] has several advantages over Rhod2 but has not been used much in central neurons [but, see 26]. However, the structural differences between the two agents may explain some differences in the detection, timing and duration of changes in [Ca 2+ ]m.…”

Changes in vitamin D and calcium-phosphorus metabolism in patients with severe acute pancreatitis

“…To date, it is believed that the physiological stimulus causes a series of calcium oscillations. For many cell types, including acinar cells, an increase in calcium concentration is a trigger for exocytosis of proteins and enzymes (16). It is proven that most of the etiological factors that cause acute pancreatitis (alcohol, hypoxia, hypercalcemia, hyperlipidemia, some pharmacological drugs) also contribute to abnormally high fluctuations in calcium levels (17).…”