PERMEABILITY TRANSITION PORE INACTIVATION GREATLY DECREASES NECROSIS IN PANCREATITIS

Abstract

Background and Aims: Necrosis is a major pathologic response of pancreatitis the mechanisms of which are poorly understood. We recently showed that mitochondrial permeabilization is a common event in models of acute pancreatitis. It results in mitochondrial depolarization, leading to intracellular ATP depletion and necrosis. The best-known mechanism of permeabilization is through opening of the mitochondrial permeability transition pore (mPTP), a multiprotein complex involving cyclophilin D (CypD). Here, we use CypD−/− mice to measure the effect of genetic inactivation of mPTP on mitochondrial death signaling and especially acinar cell necrosis in pancreatitis. Methods: Pancreatitis was induced in wild type and CypD−/− mice by 7 i.p. injections of 50 μg/kg cerulein. Necrosis was measured on H&E sections of pancreatic tissue. Changes in mitochondrial membrane potential were measured in isolated pancreatic mitochondria using TPP+ electrode. Results: CypD−/− deficiency greatly decreased the sensitivity of isolated pancreatic mitochondria to Ca2+ -induced depolarization. mPTP inactivation reduced necrosis in cerulein pancreatitis from 20 ± 2% (wild type) to 6 ± 1% (CypD−/−) mice. Pancreatitis-induced hyperamylasemia and trypsinogen activation were also significantly lower in CypD−/− than wild-type mice. Conclusions: mPTP mediates necrosis in experimental pancreatitis. The results suggest that inhibiting mPTP (eg, through CypD) is a promising strategy to treat or mitigate necrosis in pancreatitis.