Fig. 7.

Schematic depiction of current study preclinical findings. CMT2A mutant MFN2 T105M is GTPase defective and therefore exhibits impaired fusion despite normal conformational shifting (unfolded monomeric configuration shown). Reduced motility of mitochondria (green ovals) through MFN2 T105M expressing neurons, together with loss of reparative mitochondrial fusion, diminishes delivery of healthy mitochondria to neuronal termini. The consequence is neuromuscular degeneration in CMT2A mice. Burst and sustained mitofusin activation of endogenous normal MFN1 and MFN2 enables MFN-MFN oligomerization (putative toroid structure shown) and restores mitochondrial motility and respiratory fitness, thereby reversing limb denervation and normalizing neuromuscular function.