Mitofusin 2 in central nervous system disorders: Roles in mitochondrial dynamics and therapeutic Implications

Mitochondrial dynamics have been increasingly recognized as a central determinant in the pathogenesis of central nervous system (CNS) disorders. Mitofusin 2 (MFN2), a critical mitochondrial fusion protein, preserves mitochondrial network integrity and participates in fission, mitophagy, and axonal transport, thereby maintaining neuronal function and energy homeostasis. Structural features of MFN2 underpin its diverse regulatory roles, whereas MFN2 deficiency leads to mitochondrial fragmentation, metabolic dysfunction, oxidative stress, and neuronal impairment. This review summarizes the molecular mechanisms of MFN2 in the CNS and its impact on neuronal survival, synaptic function, and signaling pathways. In addition, we highlight potential MFN2-targeted interventions, including natural compounds, pharmacological agents, and emerging small-molecule activators, while also discussing disease-specific mechanisms and translational challenges such as endoplasmic reticulum (ER)-mitochondria communication abnormalities and blood-brain barrier permeability.