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O-GlcNAcylation is a dynamic post-translational modification of proteins involved in the control of intracellular signaling pathways in response to changes in nutrient availability, especially glucose concentration. To date, most research has focused on O-GlcNAcylation of proteins by the nuclear-cytoplasmic isoform of O-GlcNAc transferase (ncOGT), while the role of mitochondrial OGT (mOGT) and its effect on O-GlcNAcylation of mitochondrial proteins are poorly understood. The aim of our study was to investigate the effect of mOGT on O-GlcNAcylation of mitochondrial proteins, mitochondrial function, and energy metabolism of breast cancer cells. Herein, we used two independent proteomics-based approaches to identify mOGT-interacting partners and proteins modified by mOGT. Based on our findings, we propose that O-GlcNAcylation of proteins by mOGT is a part of the mechanism by which glucose affects mitochondrial function and cellular bioenergetics.

O-GlcNAcylation is a cell glucose sensor. The addition of O-GlcNAc moieties to target protein is catalyzed by the O-Linked N-acetylglucosamine transferase (OGT). OGT is encoded by a single gene that yields differentially spliced OGT isoforms. One of them is targeted to mitochondria (mOGT). Although the impact of O-GlcNAcylation on cancer cells biology is well documented, mOGT’s role remains poorly investigated. We performed studies using breast cancer cells with up-regulated mOGT or its catalytic inactive mutant to identify proteins specifically modified by mOGT. Proteomic approaches included isolation of mOGT protein …