| Mitofusin-2 (MFN2) | |
|---|---|
| Gene | [MFN2](/genes/mfn2) |
| UniProt ID | [O95140](https://www.uniprot.org/uniprot/O95140) |
| PDB | 6JFL, 5YEM, 5GOM |
| Molecular Weight | 99.3 kDa |
| Localization | Mitochondrial outer membrane |
| Family | Dynamin superfamily, mitofusin family |
| Disease | CMT2A, PD, AD, ALS |
Mitofusin-2 (MFN2) is a dynamin-related GTPase embedded in the mitochondrial outer membrane that mediates mitochondrial fusion, endoplasmic reticulum-mitochondria tethering, and mitophagy. Mutations in MFN2 cause Charcot-Marie-Tooth disease type 2A (CMT2A), the most common axonal form of hereditary neuropathy. MFN2 dysfunction is increasingly implicated in Parkinson's disease, Alzheimer's disease, and ALS.
MFN2 has a characteristic domain organization:
MFN2 functions through both:
MFN2 has diverse mitochondrial functions:
The ER-mitochondria tethering function is particularly important for:
MFN2 mutations cause the most common axonal hereditary neuropathy:
Common pathogenic variants:
Disease mechanisms:
MFN2 contributes to PD through:
Reduced MFN2 expression observed in PD substantia nigra.
MFN2 dysfunction in AD:
MFN2 involvement in motor neuron disease:
| Strategy | Mechanism | Status |
|---|---|---|
| Leflunomide | Enhances MFN2 expression | Phase II (CMT) |
| M1 agonist peptide | Promotes fusion | Preclinical |
| Gene therapy | AAV-MFN2 delivery | Preclinical |
| Mitochondrial antioxidants | Reduce oxidative damage | Clinical |
| HDAC6 inhibitors | Enhance mitochondrial transport | Clinical trials |
Leflunomide has shown promise in restoring mitochondrial fusion in CMT2A models[5].
Koshiba et al. Mitofusins are required for mitochondrial fusion and cell viability. 2004. ↩︎
de Brito and Scorrano. Mitofusin-2 tethers ER to mitochondria. . 2008;456(7222):605-610. 2008. ↩︎
Baloh et al. Mitofusin2 is required for axonal transport of mitochondria. J Neurosci. 2007. ↩︎
Chen and Dorn. PINK1-phosphorylated mitofusin 2 is a Parkin receptor. . 2013;340(6131):471-475. 2013. ↩︎
Rocha et al. Leflunomide promotes mitochondrial fusion in CMT2A models. J Clin Invest. 2020. ↩︎