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Knockdown of VDAC1 alleviates the cognitive dysfunction secondary to sepsis-associated encephalopathy

Mengmeng Cai1, Boxiang Du2, Yanna Si1

  • 1Department of Anesthesiology, Affiliated Nanjing Hospital of Nanjing Medical University (Nanjing First Hospital) Nanjing, Jiangsu Province, China.

American Journal of Translational Research
|August 11, 2021
PubMed

Insights

Knocking down Voltage Dependent Anion Channel 1 (VDAC1) reduces cognitive decline in sepsis-associated encephalopathy (SAE). This occurs by decreasing mitophagy and enhancing microglial efferocytosis, crucial for brain repair in sepsis.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Immunology

Background:

  • Sepsis-associated encephalopathy (SAE) is a severe neurological complication of sepsis, characterized by high morbidity and mortality.
  • Mitophagy and microglial efferocytosis are critical processes in the brain's response to sepsis.
  • Voltage Dependent Anion Channel 1 (VDAC1) regulates mitophagy, but its role in SAE is unclear.

Purpose of the Study:

  • To investigate the role of VDAC1 in SAE pathogenesis.
  • To explore whether VDAC1 influences SAE by modulating mitophagy and efferocytosis.
  • To elucidate the molecular mechanisms underlying VDAC1's effect on cognitive dysfunction in SAE.

Main Methods:

  • Establishment of a mouse model of SAE using caecal ligation and puncture (CLP).
  • Transmission electron microscopy (TEM) to assess mitophagy and efferocytosis.
  • Immunoblot tests to analyze protein interactions.
  • Behavioral tests to evaluate cognitive function.
  • VDAC1 knockdown in the SAE model.

Main Results:

  • CLP-induced SAE model exhibited increased mitophagy and decreased efferocytosis.
  • An interaction between autophagy and efferocytosis was observed.
  • Knockdown of VDAC1 significantly alleviated cognitive dysfunction in SAE mice.
  • VDAC1 knockdown led to decreased autophagy and increased efferocytosis in a PINK1/Parkin-dependent manner.

Conclusions:

  • VDAC1 plays a significant role in the progression of SAE.
  • Targeting VDAC1 may offer a therapeutic strategy for SAE.
  • VDAC1 modulates SAE-related cognitive deficits by regulating mitophagy and efferocytosis via the PINK1/Parkin pathway.
Keywords:
PINK1/ParkinVDAC1efferocytosismitophagysepsis-associated encephalopathy

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