Recent findings from our group, obtained on experimental in vivo and ex vivo models of
pancreatitis, reveal that this disease causes a profound dysfunction of key cellular organelles, lysosomes and mitochondria. We found that autophagy, the main cellular degradative, lysosome-driven process, is activated but also impaired in
acute pancreatitis because of its' inefficient progression/resolution (flux) resulting from defective function of lysosomes. One mechanism underlying the lysosomal dysfunction in
pancreatitis is abnormal processing (maturation) and activation of
cathepsins, major lysosomal
hydrolases; another is a decrease in pancreatic levels of key
lysosomal membrane proteins LAMP-1 and LAMP-2. Our data indicate that lysosomal dysfunction plays an important initiating role in
pancreatitis pathobiology. The impaired autophagy mediates vacuole accumulation in acinar cells; furthermore, the abnormal maturation and activation of
cathepsins leads to increase in intra-acinar
trypsin, the hallmark of
pancreatitis; and LAMP-2 deficiency causes
inflammation and acinar cell
necrosis. Thus, the autophagic and lysosomal dysfunctions mediate key pathologic responses of
pancreatitis. On the other hand, we showed that
pancreatitis causes acinar cell mitochondria depolarization, mediated by the permeability transition pore (PTP). Genetic (via deletion of
cyclophilin D) inactivation of PTP prevents mitochondrial depolarization and greatly ameliorates the pathologic responses of
pancreatitis. Further, our data suggest that mitochondrial damage, by stimulating autophagy, increases the demand for efficient lysosomal degradation and therefore aggravates the pathologic consequences of lysosomal dysfunction. Thus, the combined autophagic, lysosomal and
mitochondrial dysfunctions are key to the pathogenesis of
pancreatitis.