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Mitochondrial Damage

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Mitochondrial damage is therefore a serious threat to the viability of the acinar and ductal cells, as well as the pancreas as a whole. Bile acids and ethanol metabolites, among the most common pancreatitis-inducing factors, act by causing the release of stored Ca2+ within the ER and inducing extracellular Ca2+ influx. This prolonged increase in cytosolic Ca2+ concentration leads to mitochondrial Ca2+ overload and decreased intracellular ATP levels. SERCA and PMCA pumps, which remove Ca2+ from the cytoplasm, require ATP to function and will become less active; further contributing to the sustained elevation of cytosolic Ca2+ concentration. This continuous overload causes mitochondrial membrane permeabilization and overall damage to the mitochondria.…show more content…
This increases the permeability of both membranes to molecules and ions with a molecular mass less than 1.5 kDa. Increased permeability leads to loss of water potential and consequently mitochondrial swelling, membrane rupture and decreased ATP production. Three components have been identified in the make-up of the MPTP. The voltage-dependent anion channel (VDAC) in the outer membrane, the adenine nucleotide translocase (ANT) in the inner membrane and cyclophilin-D (Cyp-D) in the mitochondrial matrix. VDAC is associated with IP3R in the ER and development of Ca2+microdomains, ANT exchanges cytosolic ADP for mitochondrial ATP and Cyp-D is a peptidyl-prolyl isomerase and has a role in many functions including transcription and apoptosis. Conformational changes are induced in all three by prolonged Ca2+ overload which produce transmembrane complexes leading to MPTP formation. It was found by Mukherjee et al (2015) that MPTP opening, mediated by toxin-induced Ip3R and RyR calcium release, resulted in diminished ATP production which led to impaired Ca2+ clearance, zymogen activation, cytokine production and finally necrosis. Intracellular ATP supplementation prevented this. Mukherjee then demonstrated that when MPTP opening was inhibited either genetically or via pharmacology, all responses of acute pancreatitis were diminished…show more content…
Although this has refined the areas of research when looking for treatments, many different possibilities still remain. This is why I’ve chosen to focus on possible treatments for acute pancreatitis during my project. Several studies have already suggested targeting the PMCA, MPTP and increasing intracellular ATP levels. At this time I believe the most beneficial treatment would involve blockage or inactivation of the MPTP as it would prevent global Ca2+
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