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- Title
High glucose induces mitochondrial dysfunction independently of protein O-GlcNAcylation.
- Authors
Dassanayaka, Sujith; Readnower, Ryan D.; Salabei, Joshua K.; Long, Bethany W.; Aird, Allison L.; Yu-Ting Zheng; Muthusamy, Senthilkumar; Facundo, Heberty T.; Hill, Bradford G.; Jones, Steven P.
- 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 ß-O-linked-N-acetylglucosamine (OGlcNAc) 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 OGlcNAcylation 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 highglucose-induced changes to mitochondrial metabolism (P < 0.05) without increasing O-GlcNAcylation. Thus, increased OGlcNAcylation is neither sufficient nor necessary for highglucose-induced suppression of mitochondrial metabolism in isolated cardiomyocytes.
- Subjects
BLOOD sugar measurement; MITOCHONDRIAL pathology; DIABETES complications; GLYCOASPARAGINASE; POST-translational modification; ACYLATION
- Publication
Biochemical Journal, 2015, Vol 467, Issue 1, p115
- ISSN
0264-6021
- Publication type
Article
- DOI
10.1042/BJ20141018