title: High glucose induces mitochondrial dysfunction independently of protein O-GlcNAcylation.
abstract: Diabetes is characterized by hyperglycaemia and perturbations in intermediary metabolism. In particular, diabetes can augment flux through accessory pathways of glucose metabolism, such as the hexosamine biosynthetic pathway (HBP), which produces the sugar donor for the β-O-linked-N-acetylglucosamine (O-GlcNAc) post-translational modification of proteins. Diabetes also promotes mitochondrial dysfunction. Nevertheless, the relationships among diabetes, hyperglycaemia, mitochondrial dysfunction and O-GlcNAc modifications remain unclear. In the present study, we tested whether high-glucose-induced increases in O-GlcNAc modifications directly regulate mitochondrial function in isolated cardiomyocytes. Augmentation of O-GlcNAcylation with high glucose (33 mM) was associated with diminished basal and maximal cardiomyocyte respiration, a decreased mitochondrial reserve capacity and lower Complex II-dependent respiration (P<0.05); however, pharmacological or genetic modulation of O-GlcNAc modifications under normal or high glucose conditions showed few significant effects on mitochondrial respiration, suggesting that O-GlcNAc does not play a major role in regulating cardiomyocyte mitochondrial function. Furthermore, an osmotic control recapitulated high-glucose-induced changes to mitochondrial metabolism (P<0.05) without increasing O-GlcNAcylation. Thus, increased O-GlcNAcylation is neither sufficient nor necessary for high-glucose-induced suppression of mitochondrial metabolism in isolated cardiomyocytes.
authors: *Institute of Molecular Cardiology, Diabetes and Obesity Center, Division of Cardiovascular Medicine, Department of Medicine, University of Louisville, Louisville, KY 40202, U.S.A.
authors: Sujith
authors: S
authors: Dassanayaka
authors: *Institute of Molecular Cardiology, Diabetes and Obesity Center, Division of Cardiovascular Medicine, Department of Medicine, University of Louisville, Louisville, KY 40202, U.S.A.
authors: Ryan D
authors: RD
authors: Readnower
authors: *Institute of Molecular Cardiology, Diabetes and Obesity Center, Division of Cardiovascular Medicine, Department of Medicine, University of Louisville, Louisville, KY 40202, U.S.A.
authors: Joshua K
authors: JK
authors: Salabei
authors: *Institute of Molecular Cardiology, Diabetes and Obesity Center, Division of Cardiovascular Medicine, Department of Medicine, University of Louisville, Louisville, KY 40202, U.S.A.
authors: Bethany W
authors: BW
authors: Long
authors: *Institute of Molecular Cardiology, Diabetes and Obesity Center, Division of Cardiovascular Medicine, Department of Medicine, University of Louisville, Louisville, KY 40202, U.S.A.
authors: Allison L
authors: AL
authors: Aird
authors: *Institute of Molecular Cardiology, Diabetes and Obesity Center, Division of Cardiovascular Medicine, Department of Medicine, University of Louisville, Louisville, KY 40202, U.S.A.
authors: Yu-Ting
authors: YT
authors: Zheng
authors: *Institute of Molecular Cardiology, Diabetes and Obesity Center, Division of Cardiovascular Medicine, Department of Medicine, University of Louisville, Louisville, KY 40202, U.S.A.
authors: Senthilkumar
authors: S
authors: Muthusamy
authors: *Institute of Molecular Cardiology, Diabetes and Obesity Center, Division of Cardiovascular Medicine, Department of Medicine, University of Louisville, Louisville, KY 40202, U.S.A.
authors: Heberty T
authors: HT
authors: Facundo
authors: *Institute of Molecular Cardiology, Diabetes and Obesity Center, Division of Cardiovascular Medicine, Department of Medicine, University of Louisville, Louisville, KY 40202, U.S.A.
authors: Bradford G
authors: BG
authors: Hill
authors: *Institute of Molecular Cardiology, Diabetes and Obesity Center, Division of Cardiovascular Medicine, Department of Medicine, University of Louisville, Louisville, KY 40202, U.S.A.
authors: Steven P
authors: SP
authors: Jones
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism*; D049148:Aminoacylation; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D015536:Down-Regulation; D042963:Electron Transport Complex II / Q000037:antagonists & inhibitors / Q000378:metabolism; D004734:Energy Metabolism; D005947:Glucose / Q000009:adverse effects / Q000378:metabolism*; D006943:Hyperglycemia / Q000378:metabolism*; D008929:Mitochondria, Heart / Q000201:enzymology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000378:metabolism; D009994:Osmolar Concentration; D010085:Oxidative Phosphorylation; D011499:Protein Processing, Post-Translational; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism; D015854:Up-Regulation; D001619:beta-N-Acetylhexosaminidases / Q000235:genetics / Q000378:metabolism
chemical_list: D011994:Recombinant Proteins; D042963:Electron Transport Complex II; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase; C110628:hexosaminidase C; D001619:beta-N-Acetylhexosaminidases; D005947:Glucose; D000117:Acetylglucosamine
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