Loss-of-function mutations in the genes that encode mitochondrial fusion GTPases cause neurodegenerative disease.70
Mutations in Mfn2 cause Charcot-Marie-Tooth subtype 2A (CMT2A), a peripheral neuropathy characterized by muscle weakness and axonal degradation of sensory and motor neurons,71, 72
and hereditary motor and sensory neuropathy type VI (HMSN VI), which is clinically similar to CMT with the addition of optic atrophy and visual impairment.73
Mutations in OPA1 cause the most common form of optic atrophy, autosomal dominant optic atrophy (ADOA). Patients with ADOA exhibit progressive loss of vision and degeneration of the optic nerve and retinal ganglion cells.74
In addition, some mutations in the OPA1 GTPase domain cause ‘ADOA-plus’ phenotypes that are also characterized by deafness, sensory-motor neuropathy and muscle movement disorders.75, 76
The similarity of the symptoms caused by Mfn2 and OPA1 mutations support the idea that these proteins are functionally similar.
A recent study characterized nine Mfn2 mutants associated with CMT2A 77
, five of which cannot induce mitochondrial fusion. The ability of the other four Mfn2 mutants to fuse mitochondria suggests that Mfn2 has other roles, not related to fusion, in disease pathology. One study suggests that Mfn2 might have a role in mitochondrial trafficking, and disruption of this function could lead to peripheral axon degeneration.4
Additionally, the non-functional Mfn2 mutants promoted mitochondrial fusion in Mfn2-null cells, but not in Mfn-1 null cells77
, suggesting that Mfn1 complementation, possibly resulting from heteromeric associations,6
can rescue mitochondrial fusion. These results might also explain why mutations in Mfn2, despite being present in all cells, only affect specific neurons in CMT2A as cells with limited Mfn1 activity, and therefore less able to compensate for the Mfn2 mutations, might be more susceptible.77
Whether the levels of Mfn1 are indeed reduced in degenerating neurons in patients with CMT2A is an important question for future study.
The current mitochondrial fusion hypothesis states that Mfn2 and OPA1 are mechano-enzymes that use GTP hydrolysis to switch between distinct conformations that facilitate membrane fusion.78, 79
Intriguingly, the majority of missense mutations found in Mfn2 in patients with Charcot-Marie-Tooth disease and in OPA1 in patients with ADOA reside in the highly conserved GTPase domains () and thus, could interfere with nucleotide binding and hydrolysis. However, a number of missense mutations are also located outside the GTPase domain (Mfn2 W740S, , OPA1 L939P, ) pointing to critical residues that will be valuable starting points to further dissect the mechanisms by which these molecules recognize and fuse mitochondrial membranes.
Mutations in Mfn2 and OPA1 present in human patients
A recent case study reported a dominant-negative mutation in the helical domain of Drp1 in a human patient.80
The patient exhibited elongated and tangled mitochondria that were concentrated around the nucleus, characteristic of impaired mitochondrial fission.80
Unfortunately, the patient died 37 days after birth, displaying some symptoms that were similar to ADOA and CMT2A. Obviously, the Drp1-related disease had a much earlier onset and the impact of Drp1 mutations was much more severe than the fusion mutation diseases. Finally, mutations in GDAP1, which localizes to the outer membrane and appears to participate in Drp1-dependent mitochondrial fission, 42
cause CMT4A, another subtype of Charcot-Marie-Tooth syndrome.81-83
CMT4A combines demyelination with axonal loss and the homozygous mutation causes early onset and more severe progression.83