Increased Enzymatic O-GlcNAcylation of Mitochondrial Proteins Impairs Mitochondrial Function in Cardiac Myocytes Exposed to High Glucose

Hu, Yong; Suárez, Jorge; Fricovsky, Eduardo; Wang, Hong; Scott, Brian T.; Trauger, Sunia A.; Han, Wenlong; Hu, Ying; Oyeleye, Mary O.; Dillmann, Wolfgang H.

doi:10.1074/jbc.m808518200

Cited by 212 publications

(215 citation statements)

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“…In diabetes, increased O-GlcNAcylation of a set of cytoplasmatic and nuclear proteins has been shown, which is likely due to the activation of the hexosamine biosynthetic pathway (18,(21)(22)(23). Consistent with these observations, we found that several mitochondrial proteins are highly O-GlcNAcylated in cardiomyocytes exposed to high glucose (18,24). High glucose treatment also resulted in augmented mitochondrial fragmentation and decreased mitochondrial membrane potential (24).…”

Section: O-linked-n-acetyl-glucosamine Glycosylation (O-glcnacylationsupporting

confidence: 84%

“…Modification of other fusion/ fission proteins could also affect mitochondrial morphology and function. However, because the overall O-GlcNAc modification of cytosolic proteins is much higher than that of mitochondrial proteins (18), modulation of DRP1 function (which is a cytosolic protein) by O-GlcNAcylation is likely to have a key role in mitochondrial function. It should also be mentioned that a high glucose-mediated, sustained increase in O-GlcNAcylation has been linked to the development of diabetes-related cardiovascular complications (45,46).…”

Section: Discussionmentioning

confidence: 99%

“…Cell Culture and Treatment-Primary cultures of neonatal rat cardiomyocytes (NCMs) were prepared as described previously (18). Cells were plated onto gelatin-coated culture dishes.…”

Section: Methodsmentioning

confidence: 99%

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Modulation of Dynamin-related Protein 1 (DRP1) Function by Increased O-linked-β-N-acetylglucosamine Modification (O-GlcNAc) in Cardiac Myocytes

Gawlowski

Suárez

Scott

et al. 2012

Journal of Biological Chemistry

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163

145

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Background: DRP1 plays a significant role to control mitochondrial fission. Results: DRP1 is O-GlcNAcylated. Increased O-GlcNAcylation augments the level of the GTP-bound active form of DRP1 and induces translocation of DRP1 from cytoplasm to mitochondria. Conclusion: O-GlcNAcylation modulates DRP1 function, which has consequences for mitochondrial function. Significance: The modulation of DRP1 function by increased overall O-GlcNAcylation could play a significant role in the development of diabetic mitochondrial dysfunction.

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Section: O-linked-n-acetyl-glucosamine Glycosylation (O-glcnacylationsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

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Modulation of Dynamin-related Protein 1 (DRP1) Function by Increased O-linked-β-N-acetylglucosamine Modification (O-GlcNAc) in Cardiac Myocytes

Gawlowski

Suárez

Scott

et al. 2012

Journal of Biological Chemistry

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163

145

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“…Impaired mitochondrial O-GlcNAcylation has been associated with mitochondrial dysfunction in neurons [40] and cardiomyocytes [25,41]. Thus, we hypothesised that elevated mitochondrial O-GlcNAcylation may contribute to mitochondrial dysfunction in diabetic skeletal muscle.…”

Section: Discussionmentioning

confidence: 97%

O-GlcNAcase deficiency suppresses skeletal myogenesis and insulin sensitivity in mice through the modulation of mitochondrial homeostasis

et al. 2016

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Aims/hypothesis O-GlcNAcylation is implicated in modulating mitochondrial function, which is closely involved in regulating muscle metabolism. The presence of O-GlcNAcase (OGA), the enzyme involved in the removal of O-GlcNAc, in mitochondria was recently confirmed in rats. In the present study, we investigated the regulation of myogenesis and muscle insulin sensitivity to OGA in mice, with a focus on mitochondria. Methods C57BL/6J mice fed a high-fat diet for 4 months were used to observe mitochondrial density, activity and O-GlcNAcylation in muscle. Small interfering RNA and overexpression vectors were used to modulate protein content in vitro. Results High-fat feeding decreased the OGA level and largely increased mitochondrial O-GlcNAcylation in mouse skeletal muscle that was accompanied by decreased levels of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), decreased mitochondrial density and disrupted mitochondrial complex activities. Knockdown of OGA in C2C12 myoblasts promoted PGC-1α degradation, resulting in the suppression of mitochondrial biogenesis and myogenesis, whereas neither knockdown of O-GlcNAc transferase nor overexpression of OGA had significant effects on myogenesis. Mitochondrial dysfunction as evidenced by decreased ATP content and increased reactive oxygen species production, and increased lipid and protein oxidation was observed in both myoblasts and myotubes after OGA knockdown. Meanwhile, elevated O-GlcNAcylation through either OGA knockdown or treatment with the OGA inhibitor PUGNAc and the O-GlcNAc transferase substrate D-GlcNAc suppressed myotube insulin signalling transduction and glucose uptake. OGA overexpression had no significant effect on insulin sensitivity but sufficiently improved the insulin resistance induced by D-GlcNAc treatment. Conclusions/interpretation These data suggest that OGA can modulate mitochondrial density via PGC-1α and mitochondrial function via protein O-GlcNAcylation. In this manner, OGA appears to play a key role in myogenesis and the development of muscle insulin resistance.

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“…Ainsi, la délétion des trois premiers TPR de ncOGT n'a pas d'effet sur son activité vis-à-vis de peptides substrats, mais inhibe totalement son activité vis-à-vis de certaines protéines comme la caséine kinase II et la nucléoporine p62 [33]. En outre, l'adressage spécifique de mOGT à la mitochondrie permet également de cibler plus spécifiquement un groupe particulier de substrats [32,34]. Par ailleurs, des changements de localisation cellulaire de la forme nucléocytoplasmique de l'OGT, induits par les ligands hormonaux, permettent de diriger l'OGT vers certains substrats spécifiques.…”

Section: Isoformes De L'ogtunclassified

O-GlcNAc glycosylation et régulation de la signalisation cellulaire

Issad

2010

Med Sci (Paris)

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Le séquençage du génome humain, au début des années 2000, a révélé que notre patrimoine génétique comprenait moins de 40 000 gènes (20-25 000 gènes codant pour des protéines selon des estimations plus récentes [1]) alors que les cellules vivantes sont des systèmes sophistiqués comprenant un nombre très important d'activités biologiques complexes. Cette grande diversité des activités cellulaires, surprenante au regard du faible nombre de gènes qui codent pour les protéines, peut en partie s'expliquer par les nombreuses modifications post-traductionnelles (phosphorylation, glycosylation, sumoylation, acétylation, ubiquitinylation, nitrosylation, palmitoylation, farnésylation, méthyla-tion, ADP-ribosylation, hydroxylation, oxydation, etc.) qui augmentent de façon importante les potentialités fonctionnelles des protéines. Ces modifications contrô-lent en particulier leur localisation dans différents compartiments cellulaires et leur interaction avec différents partenaires au sein d'assemblages multimoléculaires, permettant la mise en place de réseaux de signalisation complexes. Les phosphorylations et glycosylations constituent les modifications post-traductionnelles les plus abondantes et les mieux connues. Cependant, alors que les phosphorylations sont généralement considérées comme étant des modifications rapides et réversibles, permettant à la cellule de répondre à divers stimulus et de s'adapter aux variations de son environnement, les glycosylations ont longtemps été considérées comme des modifications stables, impliquant l'ajout de chaî-nes complexes d'hydrates de carbone, qui généralement restent présentes sur la protéine mature tout au long de son existence. Ces glycosylations complexes, sur des résidus sérine/thréonine (O-glycosylations) ou asparagine (N-glycosylations), ne se rencontrent que dans certains compartiments cellulaires (réticulum endoplasmique, appareil de Golgi, face externe de la membrane plasmique) et concernent essentiellement les protéines membranaires ou sécrétées. Cependant, en 1984, en étudiant la distribution des résidus N-Acétyl-glucosamine terminaux à la surface des lymphocytes T, G. W. Hart [2] a découvert un type de glycosylation original, la O-N-Acétylglucosaminylation (O-GlcNAcylation), qui consiste en l'addition d'un monosaccharide, la N-acétyl-glucosamine, sur le groupement hydroxyl d'acides aminés sérine ou thréonine (Figure 1). Il s'est ensuite rendu compte que, contrairement aux glycosylations « classiques », cette modification était observée essentiellement dans le cytoplasme et le noyau de la cellule [3,4]. > La O-GlcNAcylation correspond à l'addition de N-Acétylglucosamine sur des résidus sérine/thréo-nine de protéines cytosoliques ou nucléaires. Elle constitue un mode de régulation post-traductionnel réversible, analogue aux phosphorylations, qui contrôle l'activité, la stabilité ou la localisation des protéines en fonction de la disponibilité en glucose. Des perturbations de la O-GlcNAcylation des protéines pourraient jouer un rôle important dans des pathologies humain...

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Increased Enzymatic O-GlcNAcylation of Mitochondrial Proteins Impairs Mitochondrial Function in Cardiac Myocytes Exposed to High Glucose

Cited by 212 publications

References 39 publications

Modulation of Dynamin-related Protein 1 (DRP1) Function by Increased O-linked-β-N-acetylglucosamine Modification (O-GlcNAc) in Cardiac Myocytes

Modulation of Dynamin-related Protein 1 (DRP1) Function by Increased O-linked-β-N-acetylglucosamine Modification (O-GlcNAc) in Cardiac Myocytes

O-GlcNAcase deficiency suppresses skeletal myogenesis and insulin sensitivity in mice through the modulation of mitochondrial homeostasis

O-GlcNAc glycosylation et régulation de la signalisation cellulaire

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