Table 1.
Mutations to genes involved in mitochondrial defects in CMT, other peripheral neuropathies, and optic atrophy.
| Gene (alphabetically) | Associated CMT neuropathy (OMIM#) | Mode of inheritance | Affected mitochondrial dynamics | Function |
|---|---|---|---|---|
| AIFM1 | CMTX4 (310490) | X-linked | Mitochondrial metabolism/apoptosis signaling | A FAD-dependent NADH oxidase with a C-terminal catalytic domain facing the IMS, cleaves under pro-apoptotic cues, moves to nucleus to initiate apoptosis |
| DHTKD1 | CMT2 (615025) | Autosomal dominant | Bioenergetics/mitochondrial metabolism | Encodes the E1 subunit of the mitochondrial amino acid degrading alpha-ketoadipic acid dehydrogenase complex |
| DNM1L | Severe infantile encephalopathy (614388) | AD, AR | Mitochondrial fission | Recruited to mitochondrial OMM by MFF, FIS1, MID49, or MID51 receptors, oligomerizes in a ring-like structure to trigger fission |
| DYNC1H1 | CMT2O (614228) SMALED (158600) |
Autosomal dominant | Mitochondrial trafficking | Subunit of dynein motor protein that performs retrograde axonal transport of mitochondria |
| GDAP1 | CMT4A (214400) CMT2K (607831) CMT2K (607831) CMTRIA (608340) |
AR AR AD AR |
Mitochondrial fission | Forms complexes with DRP1 and FIS1 to effect mitochondrial fission |
| HK1 | CMT4G or HMSN Russe (605285) | Autosomal recessive | Bioenergetics/mitochondrial metabolism | Phosphorylates glucose to G6P, couples glycolysis to OXPHOS on the OMM by interacting with VDAC and ANT |
| KIF1B | CMT2A1 (118210) | Autosomal dominant | Mitochondrial trafficking | Monomeric motor protein that performs anterograde axonal mitochondrial transport |
| KIF5A | SPG10 (604187) | Autosomal dominant | Mitochondrial trafficking | Kinesin-1 motor protein that performs anterograde axonal transport of mitochondria |
| MFN2 | CMT2A (609260) CMT2A (617087) CMT5 CMT6 (601152) |
AD AR AD AD |
Mitochondrial fusion/MAMs interaction | OMM-localized fusion protein, forms a tethering complex by homologous interaction with ER-localized MFN2 |
| MT-ATP6 | CMT2 | Autosomal dominant | Bioenergetics | ATP6 subunit of ATP synthase (OXPHOS complex V) |
| NEFL | CMT1F (607734) CMT2E (607684) |
Autosomal dominant | Mitochondrial shape/ mitochondrial trafficking | Neuron-specific component of the cytoskeleton that regulates mitochondrial shape and motility |
| OPA1 | Optic atrophy (165500) Optic atrophy plus (125250) |
Autosomal dominant | Mitochondrial fusion/bioenergetics | A mitochondrial fusion protein that also remodels cristae |
| OPA3 | Optic atrophy (165300) Costeff syndrome (258501) |
AD AR |
Mitochondrial fission/bioenergetics | Localizes to the OMM and regulates lipid metabolism, thermogenesis, and mitochondrial fission |
| PDK3 | CMTX6 (300905) | X-linked | Bioenergetics | Phosphorylates PDC, inactivating its activity, shutting down pyruvate-derived acetyl-CoA entry into the TCA |
| SIGMAR1 | dHMN | Autosomal recessive | MAMs interaction | ER chaperone protein that maintains calcium exchange between ER and mitochondria |
| SLC25A46 | CMT2 Leigh syndrome Optic atrophy |
Autosomal recessive | Mitochondrial fusion/MAMs interaction/bioenergetics | Transmembrane protein localized to OMM, mediates lipid transfer between ER and mitochondria, maintains mitochondrial lipid homeostasis and cristae |
| TUBB3 | CFEOM3 (600638) | Autosomal dominant | Mitochondrial trafficking | Polymerizes to form axonal microtubules |
| VAPB | ALS8 (608627) SMA (182980) |
Autosomal dominant | MAMs interaction | Regulates autophagosome formation at MAMs through VAPB-PTPIP51 complex |
Abbreviations: AD = autosomal dominant; ALS8 = amyotrophic lateral sclerosis 8; ANT = adenine nucleotide translocator; AIFM1 = apoptosis inducing factor mitochondria associated 1; AR = autosomal recessive; CFEOM3 = extraocular muscles type 3; CMT = Charcot-Marie-Tooth disease; dHMN = distal hereditary motor neuropathy; DHTKD1 = dehydrogenase E1 and transketolase domain containing 1; DNM1L = dynamin 1 like; DYNC1H1 = dynein cytoplasmic 1 heavy chain 1; FIS1 = fission 1 protein; G6P = glucose-6-phosphate; GDAP1 = ganglioside induced differentiation associated protein 1; HK1 = hexokinase 1; IMS = intermembrane space; KIF1B = kinesin-3 isoform B; KIF5A = kinesin-1 isoform A; MFN2 = mitofusin 2; MT-ATP6 = mitochondrially encoded ATP synthase 6; NEFL = neurofilament, light polypeptide; OMM = outer mitochondrial membrane; OPA1 = optic atrophy 1; OPA3 = optic atrophy 3; OXPHOS = oxidative phosphorylation; PDC = pyruvate dehydrogenase complex; PDK3 = pyruvate dehydrogenase kinase 3; PTPIP51 = protein tyrosine phosphatase-interacting protein 51; SIGMAR1 = sigma non-opioid intracellular receptor 1; SLC25A46 = solute carrier family 25 member 46; SMA = spinal muscular atrophy; SMALED = spinal muscular atrophy, lower extremity predominant; SPG10 = spastic paraplegia 10; TCA = tricarboxylic acid cycle; TUBB3 = class III β-tubulin; VAPB = vesicle associated membrane protein-associated protein B; VDAC = voltage-dependent anion channel.