E2F1/CDK5/DRP1 axis mediates microglial mitochondrial division and autophagy in the pathogenesis of cerebral ischemia-reperfusion injury

Abstract

	•Identification of the E2F1/CDK5/DRP1 Axis in CIRI This study reveals that the E2F1 transcription factor upregulates CDK5 expression, which in turn phosphorylates DRP1, promoting excessive mitochondrial fission and inhibiting mitophagy in microglia. This mechanism plays a critical role in cerebral ischemia-reperfusion injury (CIRI).
	•Mitochondrial Dysfunction and Neuroinflammation The activation of DRP1 leads to mitochondrial fragmentation and excessive ROS accumulation, triggering microglial activation and inflammatory responses, exacerbating neuronal apoptosis and brain injury in CIRI.
	•Therapeutic Potential of E2F1 Silencing Knockdown of E2F1 in microglia effectively reduces mitochondrial damage, restores mitophagy, suppresses inflammation, and improves neurological outcomes in a CIRI mouse model, highlighting a promising therapeutic target for ischemic stroke intervention.

Keywords

CDK5 / cerebral ischemia-reperfusion / DRP1 / E2F1 / microglia / mitochondrial division / mitophagy / single-cell transcriptome sequencing

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