Hippocampal LANCL1 attenuates postoperative cognitive dysfunction via the SIRT1/PGC-1α-mediated mitochondrial...

Area of Science:

• Neuroscience
• Mitochondrial Biology
• Gerontology

Background:

• Postoperative cognitive dysfunction (POCD) is a common complication in elderly patients undergoing surgery.
• Mitochondrial dysfunction, especially impaired biogenesis, is a key factor in POCD.
• The role of LANCL1 in POCD and its underlying mechanisms are not well understood.

Purpose of the Study:

• To investigate the role of LANCL1 in POCD.
• To explore the therapeutic potential of LANCL1 in mitigating POCD.

Main Methods:

• Aged mice underwent surgical trauma to induce POCD.
• Hippocampal LANCL1 levels were assessed.
• Lancl1 was overexpressed in the hippocampus using lentiviral vectors.
• Cognitive function, neuronal injury, mitochondrial ultrastructure, ATP content, and oxidative stress markers were evaluated.
• Single-cell sequencing was used to analyze LANCL1 expression in neurons.
• The SIRT1/PGC-1α signaling pathway was investigated.
• The effect of a SIRT1 inhibitor (EX-527) was examined.

Main Results:

• Surgical trauma led to decreased hippocampal LANCL1, cognitive deficits, and neuronal damage.
• LANCL1 overexpression ameliorated cognitive impairment and neuronal injury.
• LANCL1 enhanced mitochondrial biogenesis, indicated by increased ATP content and mtDNA-related gene expression.
• LANCL1 reduced oxidative stress markers (MDA) and improved antioxidant activity (SOD).
• LANCL1 upregulated the SIRT1/PGC-1α pathway, including NRF1 and TFAM.
• SIRT1 inhibition abolished the protective effects of LANCL1.

Conclusions:

• LANCL1 downregulation contributes to POCD by impairing mitochondrial function.
• LANCL1 overexpression protects against POCD by enhancing mitochondrial biogenesis via the SIRT1/PGC-1α pathway.
• LANCL1 represents a potential therapeutic target for preventing and treating POCD.