Mitochondria is a key cellular component. During pathophysiological stress mitochondrial function is regulated dynamically to provide cell with sufficient energy. O-GlcNAcylation, a post-translational modification associated with stress response, has been linked to beneficial effect when stimulated in shock situation, yet the link between O-GlcNAc and mitochondrial function remains poorly understood.

To evaluate mitochondrial impact of O-GlcNAc modulation.

Hearts were harvested from Wistar rat from Ctrl, shocked (LPS) and treated by NButGT, a pharmacological O-GlcNAcylation inducer. Respiration rate was assessed polarographically in isolated mitochondria. O-GlcNAcylomic was performed by mass spectrometry on cardiac tissue from rats at D0 (after birth) and D28 (suckling weaning) as well as from LPS and NButGT treated animals. Gene Ontology (GO) for cellular components (CC) of identified cardiac O-GlcNAcylated proteins from both groups were obtained by running the clusterProfileR package.

Within D0/28 groups, 647 O-GlcNAcylated proteins were found and 1012 in Ctrl/LPS/NButGT groups. Protein for subsequent analysis were selected by the log(FoldChange)>2 or<−2 with the following ratio: D28/D0 or LPS/Ctrl and LPS/NButGT. GO enrichment analysis revealed that O-glacNacyltion of, endoplasmic reticulum, mitochondria, and Golgi apparatus proteins was greater at D28. In the LPS model mitochondria and endoplasmes reticulum ranked as the top two organelles affected by NBuGT Moreover, induction of O-GlcNAcylation in isolated mitochondria rapidly stimulateed maximal mitochondrial respiration specifically in presence of Complex I substrates suggesting that O-GlcNAcylation dynamically regulate OXPHOS.

Mitochondrial O-GlcNAcylation appears to play a major role in pathophysiology. Targeting mitochondrial O-GlcNAcylation could represent a new therapeutic challenge and should be further explored.