Mechanism of mitochondrial permeability transition pore induction and damage in the pancreas: inhibition prevents acute pancreatitis by protecting production of ATP

Abstract

Objective Acute pancreatitis is caused by toxins that induce acinar cell calcium overload, zymogen activation, cytokine release and cell death, yet is without specific drug therapy. Mitochondrial dysfunction has been implicated but the mechanism not established. Design We investigated the mechanism of induction and consequences of the mitochondrial permeability transition pore (MPTP) in the pancreas using cell biological methods including confocal microscopy, patch clamp technology and multiple clinically representative disease models. Effects of genetic and pharmacological inhibition of the MPTP were examined in isolated murine and human pancreatic acinar cells, and in hyperstimulation, bile acid, alcoholic and choline-deficient, ethionine-supplemented acute pancreatitis. Results MPTP opening was mediated by toxin-induced inositol trisphosphate and ryanodine receptor calcium channel release, and resulted in diminished ATP production, leading to impaired calcium clearance, defective autophagy, zymogen activation, cytokine production, phosphoglycerate mutase 5 activation and necrosis, which was prevented by intracellular ATP supplementation. When MPTP opening was inhibited genetically or pharmacologically, all biochemical, immunological and histopathological responses of acute pancreatitis in all four models were reduced or abolished. Conclusions This work demonstrates the mechanism and consequences of MPTP opening to be fundamental to multiple forms of acute pancreatitis and validates the MPTP as a drug target for this disease.

Meta-analysis of early nutrition: the benefits of enteral feeding compared to a nil per os diet not only in severe, but also in mild and moderate acute pancreatitis

“…Bile acids, ethanol, and fatty acids were shown to be responsible for around 80% of the etiological factors initiating AP [6]. All of these factors were shown to induce a toxic calcium signal and severe mitochondrial damage in both acinar and ductal cells [3,[7][8][9][10][11]. Importantly, direct administration of ATP (i.e., energy) into the cells restored their functions and prevented cell death [12,13].…”

One compound of saponins from Disocorea zingiberensis protected against experimental acute pancreatitis by preventing mitochondria-mediated necrosis

“…3a,b). Since ATP production through electron transport chain is mediated by ΔΨm and the levels of ATP is directly correlated with the severity of pancreatic injury22. We then tested the effects of compound 1 on ATP production.…”

“…Previous studies have shown that induction of mitochondrial permeability transition pore (MPTP), featured by sudden increased permeability in inner mitochondrial membrane, loss of ΔΨm and impaired ATP production, is the central mechanism of mitochondria-mediated necrosis and the key determinant of injury in various models of AP29. The severity of AP is directly correlated with the extent of necrosis and conversely with the degree of apoptosis in several experimental models of AP922. Saponins from Panax quinquefolium have been shown to prevent MPTP opening and cell injury in a rat myocardial ischemia/reperfusion model30.…”

Chronic plus binge ethanol exposure causes more severe pancreatic injury and inflammation

“…Intraperitoneal administration of ethanol plus palmitoleic acid produces pancreatic injury characteristic of alcoholic AP. In this AP model, calcium-dependent mitochondrial dysfunction is shown to mediate ethanol-induced pancreatic injury (Huang et al , 2014; Mukherjee et al , 2016). In future studies, we will investigate whether chronic ethanol exposure alters acinar responsiveness to secretagogue or toxin stimulation; we will also determine whether chronic ethanol exposure compromises the mitochondrial function and makes it more susceptible to subsequent insults.…”