Discovery of a novel mitophagy inducer attenuating postoperative cognitive dysfunction through structure-based...

Area of Science:

• Neuroscience
• Mitochondrial Biology
• Pharmacology

Background:

• Postoperative cognitive dysfunction (POCD) is a common complication with no effective treatments.
• PTEN-induced kinase 1 (PINK1)/Parkin-mediated mitophagy is vital for mitochondrial health and reducing neuroinflammation.

Purpose of the Study:

• To discover novel mitophagy inducers for POCD treatment.
• To investigate tamarixetin as a potential therapeutic agent for POCD.

Main Methods:

• Structure-based virtual screening identified tamarixetin as a PINK1 activator.
• Molecular dynamics simulations and cellular thermal shift assays confirmed tamarixetin's binding to PINK1.
• Experiments in mice and cell lines assessed tamarixetin's effects on mitophagy, mitochondrial function, neuroinflammation, and cognitive performance.

Main Results:

• Tamarixetin selectively activated PINK1 and enhanced mitophagy in mice and neuronal/microglial cell lines.
• Treatment improved mitochondrial homeostasis, reduced oxidative stress and neuroinflammation, and restored cognitive function.
• Tamarixetin promoted PINK1 stabilization, Parkin recruitment, and mitofusin 2 ubiquitination, boosting mitophagic flux.

Conclusions:

• Tamarixetin is a novel pharmacological activator of PINK1-dependent mitophagy.
• Tamarixetin demonstrates therapeutic potential for POCD by addressing mitochondrial dysfunction and neuroinflammation.
• These findings support the development of mitophagy-targeted therapies for POCD.