Mitochondrial Dysfunction, Through Impaired Autophagy, Leads to Endoplasmic Reticulum Stress, Deregulated Lipid Metabolism, and Pancreatitis in Animal Models

Biczó, György; Végh, Eszter T.; Shalbueva, Natalia; Mareninova, Olga A.; Elperin, Jason M.; Lotshaw, Ethan; Gretler, Sophie; Lugea, Aurelia; Malla, Sudarshan; Dawson, David W.; Ruchala, Piotr; Whitelegge, Julian P.; French, Samuel W.; Wen, Li; Husain, Sohail Z.; Gorelick, Fred S.; Hegyi, Péter; Rakonczay, Zoltán; Gukovsky, Ilya; Gukovskaya, Anna S.

doi:10.1053/j.gastro.2017.10.012

Cited by 273 publications

(298 citation statements)

References 45 publications

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“…; Biczo et al . ). In this study, we have confirmed that the mPTP inhibitor NIM811 is a highly suitable compound to be tested in clinical trials.…”

Section: Discussionmentioning

confidence: 97%

“…; Biczo et al . ). It has been shown in acinar cells that bile acids (BAs) and ethanol and fatty acids (EtOH+FA) open the membrane transition pore (mPTP) channel via cyclophilin D (Cyp D) activation, keeping the channel continuously opened and thus resulting in mitochondrial depolarization, lower ATP synthesis and cell necrosis (Shalbueva et al .…”

Section: Introductionmentioning

confidence: 97%

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Novel mitochondrial transition pore inhibitor N‐methyl‐4‐isoleucine cyclosporin is a new therapeutic option in acute pancreatitis

Tóth

Maléth

Závogyán

et al. 2019

The Journal of Physiology

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Key points •Bile acids, ethanol and fatty acids affect pancreatic ductal fluid and bicarbonate secretion via mitochondrial damage, ATP depletion and calcium overload. •Pancreatitis‐inducing factors open the membrane transition pore (mPTP) channel via cyclophilin D activation in acinar cells, causing calcium overload and cell death; genetic or pharmacological inhibition of mPTP improves the outcome of acute pancreatitis in animal models. •Here we show that genetic and pharmacological inhibition of mPTP protects mitochondrial homeostasis and cell function evoked by pancreatitis‐inducing factors in pancreatic ductal cells. •The results also show that the novel cyclosporin A derivative NIM811 protects mitochondrial function in acinar and ductal cells, and it preserves bicarbonate transport mechanisms in pancreatic ductal cells. •We found that NIM811 is highly effective in different experimental pancreatitis models and has no side‐effects. NIM811 is a highly suitable compound to be tested in clinical trials. Abstract Mitochondrial dysfunction plays a crucial role in the development of acute pancreatitis (AP); however, no compound is currently available with clinically acceptable effectiveness and safety. In this study, we investigated the effects of a novel mitochondrial transition pore inhibitor, N‐methyl‐4‐isoleucine cyclosporin (NIM811), in AP. Pancreatic ductal and acinar cells were isolated by enzymatic digestion from Bl/6 mice. In vitro measurements were performed by confocal microscopy and microfluorometry. Preventative effects of pharmacological [cylosporin A (2 µm), NIM811 (2 µm)] or genetic (Ppif−/−/Cyp D KO) inhibition of the mitochondrial transition pore (mPTP) during the administration of either bile acids (BA) or ethanol + fatty acids (EtOH+FA) were examined. Toxicity of mPTP inhibition was investigated by detecting apoptosis and necrosis. In vivo effects of the most promising compound, NIM811 (5 or 10 mg kg−1 per os), were checked in three different AP models induced by either caerulein (10 × 50 µg kg−1), EtOH+FA (1.75 g kg−1 ethanol and 750 mg kg−1 palmitic acid) or 4% taurocholic acid (2 ml kg−1). Both genetic and pharmacological inhibition of Cyp D significantly prevented the toxic effects of BA and EtOH+FA by restoring mitochondrial membrane potential (Δψ) and preventing the loss of mitochondrial mass. In vivo experiments revealed that per os administration of NIM811 has a protective effect in AP by reducing oedema, necrosis, leukocyte infiltration and serum amylase level in AP models. Administration of NIM811 had no toxic effects. The novel mitochondrial transition pore inhibitor NIM811 thus seems to be an exceptionally good candidate compound for clinical trials in AP.

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“…; Biczo et al . ). In this study, we have confirmed that the mPTP inhibitor NIM811 is a highly suitable compound to be tested in clinical trials.…”

Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 97%

Novel mitochondrial transition pore inhibitor N‐methyl‐4‐isoleucine cyclosporin is a new therapeutic option in acute pancreatitis

Tóth

Maléth

Závogyán

et al. 2019

The Journal of Physiology

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“…This indicates that the cellular mechanism behind L-arginine-induced pancreatitis may lie in impaired autophagy (35). Latest findings corroborate that potential connection because mitochondrial dysfunction, an important downstream factor for impaired autophagy, was discovered as a major factor in the pathogenesis of L-arginine-induced pancreatitis (36). The involvement of free oxygen radicals, nitric oxide, or inflammatory mediators is also discussed (32).…”

Section: L-arginine-induced Cpmentioning

confidence: 75%

Genetically inducedvs.classical animal models of chronic pancreatitis: a critical comparison

et al. 2018

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Chronic pancreatitis (CP) is an utmost complex disease that is pathogenetically linked to pancreas-intrinsic ( e.g., duct obstruction), environmental-toxic ( e.g., alcohol, smoking), and genetic factors. Studying such a complex disease naturally requires validated experimental models. In the past 2 decades, the various animal models of CP usually addressed either the pancreas-intrinsic ( e.g., the caerulein model), the environmental-toxic ( e.g., diet-induced models), or the genetic component of CP. As such, these models were far from mirroring CP in its full spectrum, and the correct choice of models was vital for valid scientific conclusions on CP. The quest for mechanistic, genetic models gave rise to models based on gene modification and transgene insertion, such as the PRSS1 and the IL-1β/IL-1β models. Recently, we witnessed the development of highly exciting models that rely on the importance of autophagy in CP, that is, the murine pancreas-specific Atg5 and LAMP2 knockout models. Today, critical comparison of these several models is more important than ever for guiding research on CP in an efficient direction. The present review outlines the characteristics of the new genetic models in comparison with the well-known classic models for CP, notes the caveats in the choice of models, and also indicates novel directions for model development.-Klauss, S., Schorn, S., Teller, S., Steenfadt, H., Friess, H., Ceyhan, G. O., Demir, I. K. Genetically induced vs. classical animal models of chronic pancreatitis: a critical comparison.

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“…Autophagy is a metabolic mechanism, balancing the cell energy source and regulating tissue homeostasis. The process of autophagy is constitutively active in pancreatic disease, especially in maintaining pancreatic exocrine sufficiency . The levels of amylase and lipase in culture supernatants of pancreatic acinar cell which were treated with HYAL‐1 in the concentration of 0, 40 U/mL, 80 U/mL, 120 U/mL, 160 U/mL, and 200 U/mL were measured.…”

Section: Resultsmentioning

confidence: 99%

“…The process of autophagy is constitutively active in pancreatic disease, especially in maintaining pancreatic exocrine sufficiency. [25][26][27] The levels of amylase and lipase in culture supernatants of pancreatic acinar cell which were treated with HYAL-1 in the concentration of 0, 40 U/mL, 80 U/mL, 120 U/mL, 160 U/mL, and 200 U/mL were measured. Our data indicated that HYAL-1 increased the secretion of amylase and lipase in vitro.…”

Section: Hyal-1 Induced Pancreatic Secretion Via the Ampk And Stat3mentioning

confidence: 99%

HYAL‐1‐induced autophagy facilitates pancreatic fistula for patients who underwent pancreaticoduodenectomy

Fengyu

Yuan

et al. 2019

FASEB j.

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The main mechanism of hyaluronidase 1(HYAL-1) in the development of postoperative pancreatic fistula (POPF) after pancreatoduodenectomy (PD) was unknown. In this study, a comprehensive inventory of pre-, intra-, and postoperative clinical and biological data of two cohorts (62 pancreatic cancer [PCa] and 111 pancreatic ductal adenocarcinoma [PDAC]) which could induce POPF were retrospectively analyzed.Then, a total of 7644 genes correlated with HYAL-1 was predicted in PDAC tissues and the enriched pathway, kinase targets and biological process of those correlated genes were evaluated. Finally, a mouse pancreatic fistula (PF) model was first built and in vitro studies were performed to investigate the effects of HYAL-1 on PF progression. Our data indicated that preoperative serum HYAL-1 level, pancreatic fibrosis score, and pancreatic duct size were valuable factors for detecting POPF of Grade B and C. The serum HYAL-1 level of 2.07 mg/ml and pancreatic fibrosis score of 2.5 were proposed as the cutoff values for indicating POPF. The bioinformatic analysis and in vitro and in vivo studies demonstrated that HYAL-1 facilitates pancreatic acinar cell autophagy via the dephosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK) and signal transducers and activators of transcription 3 (STAT3) signaling pathways, which exacerbate pancreatic secretion and inflammation. In summary, the preoperative serum HYAL-1 was a significant predictor for POPF in patients who underwent PD. Tumor-induced HYAL-1 is one of core risk in accelerating PF and then promoting pancreatic secretion and acute inflammation response through the AMPK and STAT3-induced autophagy. K E Y W O R D Sautophagy, fibrosis, HYAL-1, pancreaticoduodenectomy, pancreatic fistula | 2525 LI et aL.

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Mitochondrial Dysfunction, Through Impaired Autophagy, Leads to Endoplasmic Reticulum Stress, Deregulated Lipid Metabolism, and Pancreatitis in Animal Models

Cited by 273 publications

References 45 publications

Novel mitochondrial transition pore inhibitor N‐methyl‐4‐isoleucine cyclosporin is a new therapeutic option in acute pancreatitis

Novel mitochondrial transition pore inhibitor N‐methyl‐4‐isoleucine cyclosporin is a new therapeutic option in acute pancreatitis

Genetically inducedvs.classical animal models of chronic pancreatitis: a critical comparison

HYAL‐1‐induced autophagy facilitates pancreatic fistula for patients who underwent pancreaticoduodenectomy

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