image: Nutrient deprivation inhibits mTORC1 and activates AMPK, which then dephosphorylates or phosphorylates ULK1 at different sites, leading to the activation of the ULK complex and initiation of the isolation membrane (phagophore) formation. The activated ULK complex recruits the PIK3C3 complex I (PIK3C3-CI) to the initiation sites of the autophagosome, producing the signalling molecule phosphatidylinositol 3-phosphate to promote phagophore membrane biogenesis. Concurrently, two ubiquitin-like conjugation systems, the ATG7–ATG3–ATG8/microtubule-associated protein 1A/1B-light chain 3 (LC3) and ATG12–ATG5–ATG16L1 complexes, conjugate the cytosolic form LC3 (called LC3-I) to phosphatidylethanolamine (PE), forming an autophagosome membrane-anchored LC3-II. By supplying membranes from donor sources, ATG9-mediated cycling systems, which comprise the core proteins ATG9, ATG2, VPS13D and WIPI1/2, facilitate the elongation of phagophore. A mature autophagosome will be formed when the extending phagophore closes, mediated by the ESCRT protein CHAMP2A and the ER transmembrane protein VMP1 and TMEM41B. Autophagosomes eventually fuse with the lysosome mediated by STX17–VAMP7/8–SNAP29 complex and the GTPase RAB7 and complex HOPS, resulting in the degradation of cargos within autolysosomes. Autolysosomes then undergo ALR and lysosome biogenesis mediated by TFEB. ALR, autophagic lysosome reformation; ER, endoplasmic reticulum; ESCRT, endosomal sorting complexes required for transport; TFEB, transcription factor EB.
Credit: By Wen-Xing Ding, Xiaowen Ma, Sydney Kim, Shaogui Wang and Hong-Min Ni.
Researchers are exploring a new potential avenue for pancreatitis treatment: autophagy, a cellular recycling process. Autophagy helps maintain healthy pancreatic acinar cells by removing damaged organelles like mitochondria and the endoplasmic reticulum (ER).
A new review published in eGastroenterology highlights the link between defective autophagy and pancreatitis. Impaired autophagy contributes to pancreatitis by allowing damaged organelles to accumulate within acinar cells. This accumulation disrupts cellular function and can ultimately lead to cell death.
"Autophagy plays a vital role in keeping pancreatic acinar cells healthy," explains Dr. Wen-Xing Ding, lead author of the study. "When autophagy is defective, damaged organelles build up, stressing the cells and potentially contributing to pancreatitis."
The review also explores the role of mitochondrial dysfunction and lysosomal dysfunction in pancreatitis. Mitochondria are the cell's powerhouses, and lysosomes are the compartments responsible for breaking down cellular waste. Both mitochondrial damage and impaired lysosomal function are observed in pancreatitis, further hindering the cell's ability to clear out damaged components.
The research team identified several potential therapeutic targets within the autophagy pathway. VMP1, a protein involved in both autophagy and ER-phagy (removal of damaged ER), is downregulated in pancreatitis. TFEB, a master regulator of lysosomal biogenesis and autophagy, is also decreased. Additionally, alcohol consumption disrupts autophagy by increasing ATG4B, a protease that regulates LC3-II, a key autophagy protein.
"Animal studies suggest that manipulating these proteins can influence the severity of pancreatitis," Dr. Wen-Xing Ding says." Upregulating VMP1 or TFEB, or downregulating ATG4B, enhances autophagy and protects against pancreatitis."
While further research is needed, targeting autophagy may offer a novel therapeutic approach for pancreatitis. Future studies will focus on the specific role of autophagy receptors in targeting damaged organelles during pancreatitis and the potential for manipulating autophagy to treat the disease in humans.
See the article:
Ding W-X, Ma X, Kim S, et al. Recent insights about autophagy in pancreatitis. eGastroenterology 2024;2:e100057. doi:10.1136/egastro-2023-100057
About eGastroenterology
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Journal
eGastroenterology
Article Title
Recent insights about autophagy in pancreatitis.