Journal
COMMUNICATIONS BIOLOGY
Volume 5, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s42003-022-03282-3
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Funding
- Canadian Institutes of Health Research [MOP 136999]
- Natural Sciences and Engineering Council of Canada [RGPIN 2016-09932]
- Fundamental Research of excellence in Strategic areas-Walloon Excellence in Life Sciences and Biotechnology FRFS-WELBIO (Belgium)
- Fonds National de la Recherche Scientifique FNRS (Belgium)
- Action de Recherche Concertee from Wallonia-Brussels Federation
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An in vitro assay in isolated heart mitochondria reveals that O-GlcNAcase inhibitor NButGT rapidly increases protein O-GlcNAcylation leading to increased respiratory capacity and complex I activity and decreased ROS release.
Protein O-GlcNAcylation is increasingly recognized as an important cellular regulatory mechanism, in multiple organs including the heart. However, the mechanisms leading to O-GlcNAcylation in mitochondria and the consequences on their function remain poorly understood. In this study, we use an in vitro reconstitution assay to characterize the intra-mitochondrial O-GlcNAc system without potential cytoplasmic confounding effects. We compare the O-GlcNAcylome of isolated cardiac mitochondria with that of mitochondria acutely exposed to NButGT, a specific inhibitor of glycoside hydrolase. Amongst the 409 O-GlcNAcylated mitochondrial proteins identified, 191 display increased O-GlcNAcylation in response to NButGT. This is associated with enhanced Complex I (CI) activity, increased maximal respiration in presence of pyruvate-malate, and a striking reduction of mitochondrial ROS release, which could be related to O-GlcNAcylation of specific subunits of ETC complexes (CI, CIII) and TCA cycle enzymes. In conclusion, our work underlines the existence of a dynamic mitochondrial O-GlcNAcylation system capable of rapidly modifying mitochondrial function. An in vitro assay in isolated heart mitochondria reveals that O-GlcNAcase inhibitor NButGT rapidly increases protein O-GlcNAcylation leading to increased respiratory capacity and complex I activity and decreased ROS release.
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