Organellar Dysfunction in the Pathogenesis of Pancreatitis

Abstract

Significance: Acute pancreatitis is an inflammatory disease of exocrine pancreas that carries considerable morbidity and mortality; its pathophysiology remains poorly understood. During the past decade, new insights have been gained into signaling pathways and molecules that mediate the inflammatory response of pancreatitis and death of acinar cells (the main exocrine pancreas cell type). By contrast, much less is known about the acinar cell organellar damage in pancreatitis and how it contributes to the disease pathogenesis. Recent Advances: This review summarizes recent findings from our group, obtained on experimental in vivo and ex vivo models, which reveal disordering of key cellular organelles, namely, mitochondria, autophagosomes, and lysosomes, in pancreatitis. Our results indicate a critical role for mitochondrial permeabilization in determining the balance between apoptosis and necrosis in pancreatitis, and thus the disease severity. We further investigate how the mitochondrial dysfunction (and hence acinar cell death) is regulated by Ca 2+ , reactive oxygen species, and BclxL, in relation to specific properties of pancreatic mitochondria. Our results also reveal that autophagy, the principal cellular degradative, lysosome-driven pathway, is impaired in pancreatitis due to inefficient lysosomal function, and that impaired autophagy mediates two key pathological responses of pancreatitis-accumulation of vacuoles in acinar cells and the abnormal, intra-acinar activation of digestive enzymes such as trypsinogen. Critical Issues and Future Directions: The findings discussed in this review indicate critical roles for mitochondrial and autophagic/lysosomal dysfunctions in the pathogenesis of pancreatitis and delineate directions for detailed investigations into the molecular events that underlie acinar cell organellar damage. Antioxid. Redox Signal. 15, 2699-2710.

Blockade of Multidrug Resistance-Associated Proteins Aggravates Acute Pancreatitis and Blunts Atrial Natriuretic Factor’s Beneficial Effect in Rats: Role of MRP4 (ABCC4)

“…Pancreatic injury is caused by the premature activation of digestive enzymes that the pancreas normally produces, although the early events involved in the onset of the disease still remain obscure (13). Recent studies show that impaired autophagy mediates acinar cell vacuole formation and trypsinogen activation (14,15). The combined autophagic, lysosomal and mitochondrial dysfunctions are considered key to the pathogenesis of the disease (15).…”

“…Recent studies show that impaired autophagy mediates acinar cell vacuole formation and trypsinogen activation (14,15). The combined autophagic, lysosomal and mitochondrial dysfunctions are considered key to the pathogenesis of the disease (15).…”

Autophagy and pancreatitis

“…The predominant view is that efficient, physiological autophagy is prosurvival, whereas defective autophagy promotes cell death (59,62). One mechanism whereby impaired autophagy may stimulate acinar cell death is through accumulation of damaged (e.g., uncoupled) mitochondria (33,59), as the mitochondrial damage is a key regulator of cell death in pancreatitis (34,36). Furthermore, it is possible that the accumulation of damaged mitochondria mediates the inflammatory response (e.g., through a ROS-dependent mechanism) (26,33).…”

Chronic alcohol exposure inhibits biotin uptake by pancreatic acinar cells: possible involvement of epigenetic mechanisms

“…Chronic alcohol use/exposure is associated with increased risk of pancreatic injury (16,19,30). The mechanism involved in mediating this effect is not fully understood and appears to be multifactorial.…”

“…It is believed that chronic exposure to alcohol alters the resting state of the pancreas and lowers its defense mechanisms (27,31,33). This in turn predisposes the organ to the effect of stress conditions/ injurious agents or to other cell biological events causing injury (i.e., alcohol "sensitizes" or "primes" the pancreas to subsequent injury) (16,19,30,31,33). Chronic alcohol exposure was recently shown to negatively impact biotin transport events in intestinal and renal epithelial cells (45,46), effects that may contribute to the observed low biotin levels found in chronic alcoholics (4,12).…”