Gyorgy Biczo1, Eszter T Vegh1, Natalia Shalbueva2, Olga A Mareninova2, Jason Elperin2, Ethan Lotshaw2, Sophie Gretler2, Aurelia Lugea3, Sudarshan R Malla2, David Dawson4, Piotr Ruchala4, Julian Whitelegge4, Samuel W French5, Li Wen6, Sohail Z Husain6, Fred S Gorelick7, Peter Hegyi8, Zoltan Rakonczay9, Ilya Gukovsky2, Anna S Gukovskaya10. 1. David Geffen School of Medicine, University of California at Los Angeles, California; VA Greater Los Angeles Healthcare System, Los Angeles, California; First Department of Medicine, University of Szeged, Szeged, Hungary; Department of Pathophysiology, University of Szeged, Szeged, Hungary. 2. David Geffen School of Medicine, University of California at Los Angeles, California; VA Greater Los Angeles Healthcare System, Los Angeles, California. 3. Cedars-Sinai Medical Center, Los Angeles, California. 4. David Geffen School of Medicine, University of California at Los Angeles, California. 5. Harbor-UCLA Medical Center, Torrance, California. 6. Department of Pediatric GI, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. 7. Yale University, New Haven, Connecticut. 8. Institute for Translational Medicine and First Department of Medicine, University of Pecs, Pecs, Hungary; Translational Gastroenterology Research Group, University of Szeged, Szeged, Hungary. 9. First Department of Medicine, University of Szeged, Szeged, Hungary; Department of Pathophysiology, University of Szeged, Szeged, Hungary. 10. David Geffen School of Medicine, University of California at Los Angeles, California; VA Greater Los Angeles Healthcare System, Los Angeles, California. Electronic address: agukovsk@ucla.edu.
Abstract
BACKGROUND & AIMS: Little is known about the signaling pathways that initiate and promote acute pancreatitis (AP). The pathogenesis of AP has been associated with abnormal increases in cytosolic Ca2+, mitochondrial dysfunction, impaired autophagy, and endoplasmic reticulum (ER) stress. We analyzed the mechanisms of these dysfunctions and their relationships, and how these contribute to development of AP in mice and rats. METHODS: Pancreatitis was induced in C57BL/6J mice (control) and mice deficient in peptidylprolyl isomerase D (cyclophilin D, encoded by Ppid) by administration of L-arginine (also in rats), caerulein, bile acid, or an AP-inducing diet. Parameters of pancreatitis, mitochondrial function, autophagy, ER stress, and lipid metabolism were measured in pancreatic tissue, acinar cells, and isolated mitochondria. Some mice with AP were given trehalose to enhance autophagic efficiency. Human pancreatitis tissues were analyzed by immunofluorescence. RESULTS: Mitochondrial dysfunction in pancreas of mice with AP was induced by either mitochondrial Ca2+ overload or through a Ca2+ overload-independent pathway that involved reduced activity of ATP synthase (80% inhibition in pancreatic mitochondria isolated from rats or mice given L-arginine). Both pathways were mediated by cyclophilin D and led to mitochondrial depolarization and fragmentation. Mitochondrial dysfunction caused pancreatic ER stress, impaired autophagy, and deregulation of lipid metabolism. These pathologic responses were abrogated in cyclophilin D-knockout mice. Administration of trehalose largely prevented trypsinogen activation, necrosis, and other parameters of pancreatic injury in mice with L-arginine AP. Tissues from patients with pancreatitis had markers of mitochondrial damage and impaired autophagy, compared with normal pancreas. CONCLUSIONS: In different animal models, we find a central role for mitochondrial dysfunction, and for impaired autophagy as its principal downstream effector, in development of AP. In particular, the pathway involving enhanced interaction of cyclophilin D with ATP synthase mediates L-arginine-induced pancreatitis, a model of severe AP the pathogenesis of which has remained unknown. Strategies to restore mitochondrial and/or autophagic function might be developed for treatment of AP.
BACKGROUND & AIMS: Little is known about the signaling pathways that initiate and promote acute pancreatitis (AP). The pathogenesis of AP has been associated with abnormal increases in cytosolic Ca2+, mitochondrial dysfunction, impaired autophagy, and endoplasmic reticulum (ER) stress. We analyzed the mechanisms of these dysfunctions and their relationships, and how these contribute to development of AP in mice and rats. METHODS:Pancreatitis was induced in C57BL/6J mice (control) and mice deficient in peptidylprolyl isomerase D (cyclophilin D, encoded by Ppid) by administration of L-arginine (also in rats), caerulein, bile acid, or an AP-inducing diet. Parameters of pancreatitis, mitochondrial function, autophagy, ER stress, and lipid metabolism were measured in pancreatic tissue, acinar cells, and isolated mitochondria. Some mice with AP were given trehalose to enhance autophagic efficiency. Humanpancreatitis tissues were analyzed by immunofluorescence. RESULTS:Mitochondrial dysfunction in pancreas of mice with AP was induced by either mitochondrial Ca2+ overload or through a Ca2+ overload-independent pathway that involved reduced activity of ATP synthase (80% inhibition in pancreatic mitochondria isolated from rats or mice given L-arginine). Both pathways were mediated by cyclophilin D and led to mitochondrial depolarization and fragmentation. Mitochondrial dysfunction caused pancreatic ER stress, impaired autophagy, and deregulation of lipid metabolism. These pathologic responses were abrogated in cyclophilin D-knockout mice. Administration of trehalose largely prevented trypsinogen activation, necrosis, and other parameters of pancreatic injury in mice with L-arginine AP. Tissues from patients with pancreatitis had markers of mitochondrial damage and impaired autophagy, compared with normal pancreas. CONCLUSIONS: In different animal models, we find a central role for mitochondrial dysfunction, and for impaired autophagy as its principal downstream effector, in development of AP. In particular, the pathway involving enhanced interaction of cyclophilin D with ATP synthase mediates L-arginine-induced pancreatitis, a model of severe AP the pathogenesis of which has remained unknown. Strategies to restore mitochondrial and/or autophagic function might be developed for treatment of AP.
Authors: Anna S Gukovskaya; Fred S Gorelick; Guy E Groblewski; Olga A Mareninova; Aurelia Lugea; Laura Antonucci; Richard T Waldron; Aida Habtezion; Michael Karin; Stephen J Pandol; Ilya Gukovsky Journal: Pancreas Date: 2019-04 Impact factor: 3.327
Authors: Maisam Abu-El-Haija; Anna S Gukovskaya; Dana K Andersen; Timothy B Gardner; Peter Hegyi; Stephen J Pandol; Georgios I Papachristou; Ashok K Saluja; Vikesh K Singh; Aliye Uc; Bechien U Wu Journal: Pancreas Date: 2018 Nov/Dec Impact factor: 3.327
Authors: John A Williams; Guy E Groblewski; Fred S Gorelick; Julia Mayerle; Minoti Apte; Anna S Gukovskaya Journal: Pancreas Date: 2020 May/Jun Impact factor: 3.327
Authors: Olga A Mareninova; Eszter T Vegh; Natalia Shalbueva; Carli Jm Wightman; Dustin L Dillon; Sudarshan Malla; Yan Xie; Toshimasa Takahashi; Zoltan Rakonczay; Samuel W French; Herbert Y Gaisano; Fred S Gorelick; Stephen J Pandol; Steven J Bensinger; Nicholas O Davidson; David W Dawson; Ilya Gukovsky; Anna S Gukovskaya Journal: J Clin Invest Date: 2021-08-02 Impact factor: 14.808