Enhancement of O-GlcNAcylation on Mitochondrial Proteins with 2-(4-Methoxyphenyl)ethyl-2-acetamido-2-deoxy-β-d-pyranoside, Contributes to the Mitochondrial Network, Cellular Bioenergetics and Stress Response in Neuronal Cells under Ischemic-like Conditions.

Abstract

O-GlcNAcylation is a nutrient-driven post-translational modification known as a metabolic sensor that links metabolism to cellular function. Recent evidences indicate that the activation of O-GlcNAc pathway is a potential pro-survival pathway and that acute enhancement of this response is conducive to the survival of cells and tissues. 2-(4-Methoxyphenyl)ethyl-2-acetamido-2-deoxy-β-d-pyranoside (SalA-4g), is a salidroside analogue synthesized in our laboratory by chemical structure-modification, with a phenyl ring containing a para-methoxy group and a sugar ring consisting of N-acetylglucosamine. We have previously shown that SalA-4g elevates levels of protein O-GlcNAc and improves neuronal tolerance to ischemia. However, the specific target of SalA-4g regulating O-GlcNAcylation remains unknown. To address these questions, in this study, we have focused on mitochondrial network homeostasis mediated by O-GlcNAcylation in SalA-4g's neuroprotection in primary cortical neurons under ischemic-like conditions. O-GlcNAc-modified mitochondria induced by SalA-4g demonstrated stronger neuroprotection under oxygen glucose deprivation and reoxygenation stress, including the improvement of mitochondrial homeostasis and bioenergy, and inhibition of mitochondrial apoptosis pathway. Blocking mitochondrial protein O-GlcNAcylation with OSMI-1 disrupted mitochondrial network homeostasis and antagonized the protective effects of SalA-4g. Collectively, these data demonstrate that mitochondrial homeostasis mediated by mitochondrial protein O-GlcNAcylation is critically involved in SalA-4g neuroprotection.

• Authors: Hui Xu, Mingzhi Du, Yuntian Shen, Yumin Yang, Fei Ding, Shu Yu
• Journal: Molecules (Basel, Switzerland) (Molecules) Vol. 26 Issue 19 (Sep 28 2021) ISSN: 1420-3049 [Electronic] Switzerland
• PMID: 34641427 (Publication Type: Journal Article)

Chemical References

• 2-(4-methoxyphenyl)ethyl-2-acetamido-2-deoxyglucopyranoside
• Mitochondrial Proteins
• Neuroprotective Agents
• Glucose
• Oxygen
• Acetylglucosamine

Topics

• Acetylglucosamine (analogs & derivatives, pharmacology)
• Animals
• Energy Metabolism
• Glucose (metabolism)
• Glycosylation
• Homeostasis
• Ischemia (metabolism, pathology, prevention & control)
• Mitochondria (drug effects, metabolism, pathology)
• Mitochondrial Proteins (chemistry, drug effects)
• Neurons (drug effects, metabolism, pathology)
• Neuroprotective Agents (pharmacology)
• Oxygen (metabolism)
• Protein Processing, Post-Translational
• Rats
• Rats, Sprague-Dawley