Mitochondrial Dysfunction, Through Impaired Autophagy, Leads to Endoplasmic Reticulum Stress, Deregulated Lipid Metabolism, and Pancreatitis in Animal Models
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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 Ca 2+, 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 Ca 2+ overload or through a Ca 2+ 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.
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Mitochondrial dysfunction can lead to ER stress through impaired autophagy.
“Also mitochondrial dysfunction can lead to ER stress through impaired autophagy [4].”
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“Also mitochondrial dysfunction can lead to ER stress through impaired autophagy [4].”
Background
- Authors
- Biczo, G., Vegh, E. T., Shalbueva, N., Mareninova, O. A., Elperin, J., Lotshaw, E., Gretler, S., Lugea, A., Malla, S. R., Dawson, D., Ruchala, P., Whitelegge, J., French, S. W., Wen, L., Husain, S. Z., Gorelick, F. S., Hegyi, P., Rakonczay, Z., Gukovsky, I., & Gukovskaya, A. S.
- Affiliations
- University of California, Los Angeles (US)
- Cedars-Sinai Medical Center (US)
- Harbor–UCLA Medical Center (US)
- University of Pittsburgh (US)
- Yale University (US)
- Corresponding author
- Gukovskaya, Anna S.
- ORCID
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2018-02
- Volume
- 154
- Issue
- 3
- Pages
- 689-703
- ISSN
- 0016-5085 (ISSN-L)
- PMC
- PMC6369139
- OpenAlex
- W2766966618
- Cited by
- 406
- References
- 45
- Citations by year
- 2026: 33 · 2025: 63 · 2024: 69 · 2023: 58 · 2022: 60 · 2021: 42 · 2020: 34 · 2019: 32 · 2018: 14 · 2017: 1
- FWCI
- 22.68
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- SZTE Publicatio Repozitórium (University of Szeged) (acceptedVersion, other-oa)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- NIH (P01DK098108)
- Rosztoczy Foundation
- Topics
- Health Sciences › Medicine › Surgery › Pancreatitis Pathology and Treatment
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Keywords
- acute pancreatitis, mitochondrial dysfunction, autophagy, endoplasmic reticulum stress, lipid metabolism, cyclophilin D, ATP synthase, L-arginine-induced pancreatitis, trehalose, mitochondrial depolarization, mitochondrial fragmentation, trypsinogen activation, pancreatitis pathogenesis
- MeSH terms
- Peptidyl-Prolyl Isomerase F, Acute Disease, Animals, Arginine, Autophagy, Bile Acids and Salts, Ceruletide, Choline Deficiency, Disease Models, Animal, Ethionine, Humans, Mice, Inbred C57BL, Mitochondria, Pancreas, Pancreatitis, Phenotype, Time Factors, Trehalose, Mice, Knockout, Calcium Signaling, Genetic Predisposition to Disease, Cyclophilins, Mitochondrial Proton-Translocating ATPases, Lipid Metabolism, Rats, Membrane Potential, Mitochondrial, Endoplasmic Reticulum Stress
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