Nitration of Drp1 provokes mitophagy activation mediating neuronal injury in experimental autoimmune...

Area of Science:

• Neuroscience
• Cell Biology
• Immunology

Background:

• Autophagy and mitophagy are implicated in neurodegeneration and motor deficits in multiple sclerosis (MS).
• Dynamin-related protein 1 (Drp1) recruitment to mitochondria is essential for initiating mitophagy.
• The role of peroxynitrite (ONOO-) in MS pathology and its mechanisms are not fully understood.

Purpose of the Study:

• To investigate if ONOO- mediates Drp1 assembly in mitochondria, induces mitophagy, and exacerbates MS pathology using an experimental autoimmune encephalomyelitis (EAE) animal model.
• To explore the therapeutic potential of targeting ONOO- in MS.

Main Methods:

• Utilized the EAE mouse model to study autophagy/mitophagy, Drp1 dynamics, and ONOO- production.
• Administered Mdivi-1 (mitochondrial division/mitophagy inhibitor) and a peroxynitrite decomposition catalyst (PDC) to assess their effects on EAE pathology.
• Analyzed Drp1 nitration, mitochondrial recruitment, and mitophagy activation in response to ONOO-.

Main Results:

• Autophagy/mitophagy, axonal damage, apoptosis, and disease progression were increased in active EAE mice, and attenuated by Mdivi-1.
• Increased ONOO- production correlated with Drp1 mitochondrial recruitment, PINK1/Parkin-mediated mitophagy, axonal degeneration, and neuronal cell death.
• These pathological changes were reversed by PDC treatment.
• ONOO- induced Drp1 nitration, promoting its assembly and mitochondrial recruitment, thereby activating mitophagy and contributing to EAE pathology.

Conclusions:

• ONOO- acts as a key mediator in the nitration and assembly of Drp1, facilitating mitophagy activation.
• Targeting ONOO--mediated Drp1 assembly and mitochondrial recruitment presents a potential therapeutic strategy for multiple sclerosis treatment.