MFN2 has been shown by electron microscopy (EM) to accumulate in contact regions between adjacent mitochondria, supporting their role in mitochondrial fusion.

[10][11] Seminal studies revealed that both, MFN1 and MFN2 spanning from the OMM of two opposing mitochondria, physically interact in trans, by the formation of antiparallel dimers between their HR2 domains.

[18] Conditional MFN2 knockout mice show degeneration in the Purkinje cells of the cerebellum, as well as improperly localized mitochondria in the dendrites.

MFN2 has been proposed to be essential for the transport of mitochondria along axons, being involved in their attachment to microtubules through interaction with the two main motor proteins Miro and Milton.

[20] Other intracellular pathways, such as cell cycle progression, maintenance of mitochondrial bioenergetics, apoptosis, and autophagy, have been demonstrated to be modulated by MFN2.

The importance of a regulated mitochondrial morphology in cell physiology makes immediately clear the potential impact of MFN2 in the onset/progression of different pathological conditions.

MFN2 mutations are linked to neurological disorders characterized by a wide clinical phenotype that involves the central and peripheral nervous system.

[21][22] The impairment of the former is rarer while neuropathy forms are more frequent and severe, involving both legs and arms, with weakness, sensory loss, and optical atrophy.

Another important cell feature altered in the presence of MFN2 mutations is mitochondrial transport and indeed current models propose this defect as the major cause of CMT2A.

Recent studies have also shown that mitochondria arrest fusion by down-regulating MFN2 in obesity and diabetes, which leads to a fragmented mitochondrial network.

[37] A modest cardiac hypertrophy, associated to a tendency of MFN2-deprived mitochondria was observed caused by an increased resistance to Ca2+-mediated cell death stimuli.

[38] Furthermore, reduced expression of MFN2 and subsequent disruption of sarcoplasmic reticulum-mitochondrial contacts was observed to associate with atrial fibrillation in Drosophila.

[39] While it is undisputed the importance of MFN2 in cardiomyocytes physiology, clarification of whether its pro-fusion activity or other functionalities of the protein are involved will require further investigations.

[41] All these factors lead to a poor cancer prognosis and, therefore, novel therapeutic strategies for targeting and eradicating MDR TNBC cells are required.