Mitofusin-2

Mitofusin-2 (MFN2) is a mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion, playing a central role in mitochondrial dynamics and metabolism (UniProt: O95140). The protein regulates the balance between mitochondrial fusion and fission, with overexpression inducing mitochondrial network formation. MFN2 is also involved in mitophagy, clearance of damaged mitochondria, and control of the unfolded protein response during endoplasmic reticulum stress.

MFN2 mutations are associated with several neurological disorders, including autosomal dominant and recessive forms of Charcot-Marie-Tooth disease (CMT2A2A, CMT2A2B) and hereditary motor and sensory neuropathy with optic atrophy (HMSN6A) (UniProt: O95140). These peripheral neuropathies are characterized by progressive axonal degeneration and distal muscle weakness.

In Alzheimer's Disease, MFN2 is significantly downregulated in post-mortem AD brain tissue compared to age-matched controls, with a mean log2 fold-change of −0.27 (Chaparral AD proteomics). This reduction in mitochondrial fusion capacity may contribute to impaired mitochondrial quality control and cellular energy metabolism in AD pathology.