title: AMPK regulates ER morphology and function in stressed pancreatic β-cells via phosphorylation of DRP1.
abstract: Experimental lipotoxicity constitutes a model for β-cell demise induced by metabolic stress in obesity and type 2 diabetes. Fatty acid excess induces endoplasmic reticulum (ER) stress, which is accompanied by ER morphological changes whose mechanisms and relevance are unknown. We found that the GTPase dynamin-related protein 1 (DRP1), a key regulator of mitochondrial fission, is an ER resident regulating ER morphology in stressed β-cells. Inhibition of DRP1 activity using a GTP hydrolysis-defective mutant (Ad-K38A) attenuated fatty acid-induced ER expansion and mitochondrial fission. Strikingly, stimulating the key energy-sensor AMP-activated protein kinase (AMPK) increased the phosphorylation at the anti-fission site Serine 637 and largely prevented the alterations in ER and mitochondrial morphology. Expression of a DRP1 mutant resistant to phosphorylation at this position partially prevented the recovery of ER and mitochondrial morphology by AMPK. Fatty acid-induced ER enlargement was associated with proinsulin retention in the ER, together with increased proinsulin/insulin ratio. Stimulation of AMPK prevented these alterations, as well as mitochondrial fragmentation and apoptosis. In summary, DRP1 regulation by AMPK delineates a novel pathway controlling ER and mitochondrial morphology, thereby modulating the response of β-cells to metabolic stress. DRP1 may thus function as a node integrating signals from stress regulators, such as AMPK, to coordinate organelle shape and function.
authors: MD, Endocrinology and Metabolism Service, Department of Medicine, Hadassah-Hebrew University Medical Center, PO Box 12000, Jerusalem 91120. gleib@hadassah.org.il.
authors: Jakob D
authors: JD
authors: Wikstrom
authors: Tal
authors: T
authors: Israeli
authors: Etty
authors: E
authors: Bachar-Wikstrom
authors: Avital
authors: A
authors: Swisa
authors: Yafa
authors: Y
authors: Ariav
authors: Meytal
authors: M
authors: Waiss
authors: Daniel
authors: D
authors: Kaganovich
authors: Yuval
authors: Y
authors: Dor
authors: Erol
authors: E
authors: Cerasi
authors: Gil
authors: G
authors: Leibowitz
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000473:pathology; D034281:Dynamins / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000201:enzymology* / Q000473:pathology; D059865:Endoplasmic Reticulum Stress; D004789:Enzyme Activation; D050417:Insulin-Secreting Cells / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000201:enzymology; D009765:Obesity / Q000201:enzymology / Q000473:pathology; D053140:Organelle Shape; D010168:Palmitates / Q000494:pharmacology; D010766:Phosphorylation; D056811:Unfolded Protein Response
chemical_list: D010168:Palmitates; D000263:Adenylate Kinase; C486391:Dnm1l protein, mouse; D034281:Dynamins
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