Relevance of the enzymatic O-GlcN-Acylation of mitochondrial proteins to the development of cardiac dysfunction in diabetes mellitus.
Final Report Abstract
The central hypothesis of this proposal was that diabetes mellitus (DM) induced increased O-linked-N-acetyl-glucosamine glycosylation (O-GlcNAcylation) of cardiac mitochondrial proteins results in mitochondrial dysfunction, which can be reverted to towards normal in spite of persistent hyperglycemia or DM. During the DFG-sponsored fellowship obtained results show that global increased O-GlcNAcylation results in mitochondrial dysfunction. 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, it could be shown 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. Unexpected difficulties occurred regarding the overexpression of the transgenes for the in vivo experiments. Because the overexpression of the transgenes did not work no data were obtained for the planned in vivo rescue experiments. However, the in vitro results indicate that the impact of excessive overall O-GlcNAcylation on DRP1 function could play a significant role in the development of diabetic mitochondrial dysfunction.
Publications
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Am J Physiol Regul Integr Comp Physiol. 2011, R1296-302. Regulation of mitochondrial morphology and function by O-GlcNAcylation in neonatal cardiac myocytes
Makino A, Suarez J, Gawlowski T, Han W, Wang H, Scott BT, Dillmann WH
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J Biol Chem, 2012, 287:30024-34. Modulation of dynamin-related protein 1 (DRP1) function by increased O-linked-β-N-acetylglucosamine modification (O-GlcNAc) in cardiac myocytes
Gawlowski T, Suarez J, Scott B, Torres-Gonzalez M, Wang H, Schwappacher R, Han X, Yates J, Hoshijima M, Dillmann WH
