Neuroinflammation-mediated mitochondrial dysregulation involved in postoperative cognitive dysfunction

Area of Science:

• Neuroscience
• Cell Biology
• Pathology

Background:

• Postoperative cognitive dysfunction (POCD) is linked to neuroinflammation following surgery.
• Impaired mitochondrial function is a hallmark of neuronal degeneration in POCD.
• Dynamin-related protein 1 (DRP1) regulates mitochondrial dynamics and synapse formation.

Purpose of the Study:

• To investigate the role of DRP1-regulated mitochondrial dynamics in POCD.
• To explore the relationship between DRP1, mitochondrial function, and neuroinflammation in POCD.

Main Methods:

• Aged mice underwent laparotomy; primary neurons and SH-SY5Y cells were exposed to tumor necrosis factor (TNF).
• Assessed DRP1 activation, mitochondrial fragmentation, and mitochondrial function.
• Utilized DRP1 inhibitor (Mdivi-1), DRP1 knockdown (siRNA), and calcineurin inhibitor (FK506).

Main Results:

• Surgery and TNF exposure increased DRP1 activation and mitochondrial fragmentation.
• Mdivi-1 reduced fragmentation but impaired mitochondrial function and neurite growth.
• FK506 mitigated mitochondrial dysfunction and improved neurite growth and learning ability, independent of DRP1.

Conclusions:

• DRP1 activation contributes to mitochondrial dysfunction in POCD, but direct inhibition is detrimental.
• Calcineurin activity mediates DRP1 activation and subsequent mitochondrial dysfunction.
• Modulating neuronal metabolism via calcineurin inhibition offers a promising therapeutic strategy for POCD.