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Publications

Journal Article Ppublish

PubMed: 40250747 DOI: 10.1016/j.brainres.2025.149647

Effects of mitochondrial O-GlcNAcylation in pericytes after mechanical injury.

Brain Res 1859:149647

Authors: Ji Hyun Park, Dong Bin Back, Shuzhen Guo, Masayoshi Tanaka, Hajime Takase, Michael J Whalen, Ken Arai, Kazuhide Hayakawa, Eng H Lo

Affiliations

  • Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
  • Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
  • Department of Pediatrics, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
  • Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
  • Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.

Abstract

Damage to vascular cells comprise an important part of traumatic brain injury (TBI) but the underlying pathophysiology remains to be fully elucidated. Here, we investigate the loss of O-Linked β-N-acetylglucosamine(O-GlcNAc) modification (O-GlcNAcylation) and mitochondrial disruption in vascular pericytes as a candidate mechanism. In mouse models in vivo, TBI rapidly induces vascular oxidative stress and down-regulates mitochondrial O-GlcNAcylation. In pericytes but not brain endothelial cultures in vitro, mechanical stretch injury down-regulates mitochondrial O-GlcNAcylation. This is accompanied by disruptions in mitochondrial dynamics, comprising a decrease in mitochondrial fusion and an increase in mitochondrial fission proteins. Pharmacologic rescue of endogenous mitochondrial O-GlcNAcylation with an O-GlcNAcase inhibitor Thiamet-G or addition of exogenous O-GlcNAc-enhanced extracellular mitochondria ameliorates the mitochondrial disruption in pericytes damaged by mechanical injury. Finally, in a pericyte-endothelial co-culture model, mechanical injury increased trans-cellular permeability; adding Thiamet-G or O-GlcNAc-enhanced extracellular mitochondria rescued trans-cellular permeability following mechanical injury. These proof-of-concept findings suggest that mitochondrial O-GlcNAcylation in pericytes may represent a novel therapeutic target for ameliorating oxidative stress and vascular damage after mechanical injury following TBI.

MeSH

Pericytes, Stress, Physiological, Brain, Mitochondria, Oxidative Stress