A small molecule M1 promotes optic nerve regeneration to restore target-specific neural activity and visual function

Area of Science:

• Neuroscience
• Mitochondrial Biology
• Regenerative Medicine

Background:

• Axon regeneration is crucial for nervous system repair but is energy-intensive, relying on mitochondrial transport.
• Peripheral nervous system (PNS) axon regeneration shows robust mitochondrial transport, unlike the central nervous system (CNS).
• Targeting mitochondria is a potential strategy for enhancing neural repair.

Purpose of the Study:

• To investigate the effects of a small molecule M1 on axon regeneration, neural activity, and visual function recovery.
• To explore M1's impact on mitochondrial dynamics and transport in both PNS and CNS neurons.
• To determine the necessity of mitochondrial dynamics for M1-induced CNS axon regeneration.

Main Methods:

• Treatment with M1 following optic nerve crush (ONC) in a mouse model.
• Ex vivo time-lapse imaging and kymograph analysis of mitochondrial transport in peripheral axons.
• Assessment of axonal regeneration, neural activity in the superior colliculus (SC), and visual function recovery (pupillary light reflex, looming visual stimuli response).
• Gene expression analysis of mitochondrial fusion and axonal transport proteins.
• Knockdown of mitochondrial genes (Opa1, Mfn2) to assess M1's mechanism of action.

Main Results:

• M1 significantly enhanced mitochondrial fusion, transport, motility, and velocity in peripheral axons.
• M1 promoted sustained axon regeneration through the optic chiasm into subcortical areas after ONC.
• M1 restored neural activity in the SC and led to complete recovery of the pupillary light reflex and visual responses.
• M1 upregulated mitochondrial fusion and axonal transport machinery genes without inducing inflammation.
• Knockdown of Opa1 or Mfn2 abolished M1's growth-promoting effects, highlighting the role of mitochondrial dynamics.

Conclusions:

• M1 effectively promotes axon regeneration and functional recovery after optic nerve injury by enhancing mitochondrial dynamics and transport.
• Sustained mitochondrial dynamics in axons are essential for successful CNS axon regeneration.
• M1 represents a promising therapeutic candidate for treating optic nerve damage and potentially other CNS injuries.