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MCU knockdown mitigates post-stroke neuroinflammation through SLC33A1-mediated reduction of NR4A1 acetylation

Zhou Zhou1, Lijuan Liu1, Yicong Zhou2

  • 1Department of Neurology, The First Hospital of Hebei Medical University, No. 89, Donggang Road, Yuhua District, Shijiazhuang, Hebei 050031, China.

Brain Research Bulletin
|December 6, 2025
PubMed

Insights

Mitochondrial calcium uniporter (MCU) knockdown reduces stroke injury and brain inflammation. This neuroprotective effect is mediated by SLC33A1, which controls NR4A1 acetylation, offering a potential anti-inflammatory therapy for stroke recovery.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Immunology

Background:

  • Post-stroke neuroinflammation exacerbates brain injury and hinders recovery.
  • Mitochondrial calcium uniporter (MCU) knockdown previously showed protection against ischemic injury.
  • Transcriptomic data suggested a role for NR4A1 in MCU-mediated effects.

Purpose of the Study:

  • To elucidate the mechanism by which MCU knockdown confers neuroprotection post-stroke.
  • To investigate the interaction between MCU, NR4A1, and inflammatory pathways in microglia.

Main Methods:

  • Utilized a mouse middle cerebral artery occlusion (MCAO) model for ischemic stroke.
  • Employed microglial oxygen-glucose deprivation/reoxygenation (OGD/R) models.
  • Conducted protein interaction assays (immunoprecipitation-mass spectrometry) and acetylation assays.

Main Results:

  • MCU knockdown significantly reduced infarct volume and improved neurological function in MCAO mice.
  • MCU knockdown suppressed microglial inflammatory cytokine expression.
  • Identified SLC33A1 as a novel MCU interactor, mediating reduced NR4A1 acetylation and attenuated inflammation.

Conclusions:

  • MCU knockdown mitigates cerebral infarction and suppresses microglial inflammation.
  • The mechanism involves SLC33A1-dependent regulation of NR4A1 acetylation.
  • MCU knockdown represents a promising strategy for post-stroke anti-inflammatory intervention.
Keywords:
AcetylationCerebral infarctionMCUNR4A1SLC33A1

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