title: Modulation of dynamin-related protein 1 (DRP1) function by increased O-linked-β-N-acetylglucosamine modification (O-GlcNAc) in cardiac myocytes.
abstract: O-linked-N-acetyl-glucosamine glycosylation (O-GlcNAcylation) of the serine and threonine residues of cellular proteins is a dynamic process and affects phosphorylation. Prolonged O-GlcNAcylation has been linked to diabetes-related complications, including mitochondrial dysfunction. Mitochondria are dynamically remodeling organelles, that constantly fuse (fusion) and divide (fission). An imbalance of this process affects mitochondrial function. In this study, we found that dynamin-related protein 1 (DRP1) is O-GlcNAcylated in cardiomyocytes at threonine 585 and 586. O-GlcNAcylation was significantly enhanced by the chemical inhibition of N-acetyl-glucosaminidase. Increased O-GlcNAcylation decreases the phosphorylation of DRP1 at serine 637, which is known to regulate DRP1 function. In fact, increased O-GlcNAcylation augments the level of the GTP-bound active form of DRP1 and induces translocation of DRP1 from the cytoplasm to mitochondria. Mitochondrial fragmentation and decreased mitochondrial membrane potential also accompany the increased O-GlcNAcylation. In conclusion, this report shows, for the first time, that O-GlcNAcylation modulates DRP1 functionality in cardiac muscle cells.
authors: Department of Medicine, University of California, San Diego, La Jolla, CA 92039, USA.
authors: Thomas
authors: T
authors: Gawlowski
authors: Jorge
authors: J
authors: Suarez
authors: Brian
authors: B
authors: Scott
authors: Moises
authors: M
authors: Torres-Gonzalez
authors: Hong
authors: H
authors: Wang
authors: Raphaela
authors: R
authors: Schwappacher
authors: Xuemei
authors: X
authors: Han
authors: John R
authors: JR
authors: Yates
authors: Masahiko
authors: M
authors: Hoshijima
authors: Wolfgang
authors: W
authors: Dillmann
mesh_terms: D000107:Acetylation; D000117:Acetylglucosamine / Q000235:genetics / Q000378:metabolism*; D000118:Acetylglucosaminidase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D048909:Diabetes Complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D034281:Dynamins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000235:genetics; D051379:Mice; D008929:Mitochondria, Heart / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D028361:Mitochondrial Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000235:genetics; D021381:Protein Transport / Q000235:genetics
chemical_list: D009124:Muscle Proteins; D000118:Acetylglucosaminidase; C486391:Dnm1l protein, mouse; D034281:Dynamins; D000117:Acetylglucosamine