PLD3-mediated Mitophagy Attenuates Neuronal Ferroptosis and Promotes Functional Recovery after Spinal Cord Injury

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Ferroptosis, a form of cell death, is a key contributor to secondary injury following spinal cord injury (SCI).
• Oxidative stress, stemming from ischemia and hypoxia, drives ferroptosis after SCI.
• The precise role and mechanisms of Phospholipase D3 (PLD3) in SCI-induced ferroptosis are not well understood.

Purpose of the Study:

• To investigate the function of PLD3 in the pathological processes of SCI.
• To elucidate the underlying mechanisms by which PLD3 influences ferroptosis and mitochondrial function in SCI.

Main Methods:

• Utilized a mouse model of SCI and proteomic/biochemical analyses.
• Employed an oxygen-glucose deprivation (OGD) model using PC12 cells.
• Investigated the role of the PINK1/Parkin pathway and mitophagy in PLD3-mediated protection.

Main Results:

• PLD3 expression was significantly reduced in injured spinal cord tissue and OGD-treated PC12 cells, correlating with increased oxidative stress and ferroptosis markers.
• Overexpression of neuronal PLD3 in vivo promoted spinal cord repair and functional recovery.
• PLD3 overexpression in PC12 cells alleviated OGD-induced mitochondrial dysfunction, oxidative stress, and ferroptosis, partly through activating the PINK1/Parkin pathway and enhancing mitophagy.

Conclusions:

• PLD3 plays a protective role against ferroptosis and mitochondrial dysfunction following SCI.
• PLD3 overexpression preserves mitochondrial homeostasis via PINK1/Parkin-mediated mitophagy.
• PLD3 represents a potential therapeutic target for mitigating secondary injury after spinal cord injury.