mitofusins

Mitofusins are large guanosine triphosphatase (GTPase) proteins of the mitochondrial outer membrane that regulate mitochondrial fusion and network morphology. They are encoded by the MFN1 and MFN2 genes in mammals. Both proteins share domain organization: an N-terminal GTPase domain, two coiled-coil heptad-repeat regions (HR1 and HR2) that mediate tethering, and a C-terminal membrane-anchoring region that localizes the protein to the outer mitochondrial membrane.

Mechanism: MFN1 and MFN2 act in trans, on adjoining mitochondria, to tether membranes via interactions between their HR1/HR2 domains, followed by GTP hydrolysis–driven conformational changes that fuse the outer membranes. Fusion of the outer membranes is coordinated with inner membrane fusion by OPA1 and other factors, enabling complete mitochondrial fusion and exchange of lipids and matrix contents. Mitofusins participate in maintaining mitochondrial networks, distribution, and function, and are regulated by cellular cues including phosphorylation and ubiquitination. They are also involved in regulation of mitochondrial contacts with the endoplasmic reticulum and in mitophagy; for example, PINK1/Parkin-mediated ubiquitination targets MFN2 to promote selective removal of damaged mitochondria.

Clinical significance: Pathogenic variants in MFN2 are the most common cause of Charcot–Marie–Tooth disease type 2A, a hereditary neuropathy. MFN1 mutations are rarer. Abnormal mitofusin function is linked to alterations in mitochondrial morphology and cellular energy metabolism.