Article
The role of mitochondrial fusion in optic nerve regeneration and targeted intervention strategies
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Authors
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Jiahui Tang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University
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Z. Liu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University
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Y.Q. Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University
| Published: | May 9, 2025 |
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Outline
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Objective: Investigate the role of mitochondrial fusion in promoting RGC survival and axon regeneration and explore intervention strategies for potential clinical applications using mRNA drug delivery and small-molecule compounds.
Methods: 1. Mitochondrial Homeostasis in RGCs Post Optic Nerve Injury: The optic nerve crush (ONC) model used electron microscopy and immunofluorescence to study mitochondrial morphology in RGCs.
Analyzed the expression and activity of mitochondrial fusion-related proteins (OPA1, OMA1, MFN1/2) through immunofluorescence and enzyme activity assays.
2. Impact of Mitochondrial Fusion on RGC Survival and Axon Regeneration: Inner Membrane Fusion: Administered adeno-associated virus (AAV2) to overexpress OPA1 or knockdown OMA1 in RGCs 2 weeks before ONC. Evaluated RGC survival using RBPMS immunofluorescence and axon regeneration through CTB labeling.
Outer Membrane Fusion: Overexpressed MFN1 and MFN2 in RGCs using AAV2 in the ONC model to analyze effects on RGC survival and optic nerve regeneration.
3. Post-Injury Intervention Strategies Based on Mitochondrial Fusion: Administered MFN agonist MASM7 or lipid nanoparticle-encapsulated MFN1 mRNA post-ONC to assess effects on RGC survival and optic nerve regeneration.
Results: 1. Optic nerve injury led to increased mitochondrial fragmentation in RGCs and decreased health scores, with significant activation of OMA1 and elevated cleavage of OPA1.
2. Promoting inner membrane fusion preserved RGC survival but did not induce axon regeneration. Promoting outer membrane fusion supported long-term RGC survival and enabled full-length optic nerve regeneration.
3. Post-injury treatment with MFN1 small molecule agonists or mRNA therapy effectively preserved RGC survival and stimulated optic nerve regeneration.
Discussion: This study offers the initial evidence of the role of mitochondrial fusion in optic nerve regeneration and validates promising intervention strategies for clinical translation after injury.
