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Saneto. J Transl Genet Genom 2020;4:384-428 I http://dx.doi.org/10.20517/jtgg.2020.40 Page 407

protein is MFN-2 as well as another linking protein from the ER named ER-resident vesicle-associated
membrane protein-associated protein V (VAPB) with another outer membrane protein, tyrosine
phosphatase-interacting protein 51 (PTPIP51). The interaction of mitochondria at these specialized ER
membrane sites are involved in calcium flux into mitochondria and important for calcium homeostasis
and metabolism. Calcium imbalance may initiate mitophagy or at physiological concentrations enhance
oxidative phosphorylation. In addition to mitochondria being associated with the ER at specific positions,
mitochondrial also traverse the cytosol and axons on dynein and kinesin tracks.

Fusion and fission are key processes regulating normal mitochondrial function and preventing disease [255] .
Fission is performed by the dynamin-related protein 1 (DMN1L, also known as DRP1). This protein
translocates from the cytosol to the mitochondria outer membrane and binds to mitochondrial fission
factor (MFF), mitochondrial dynamics protein of 49 kDA (MID49), and fission 1 protein (FIS1). The
binding of DMN1L creates a band around the mitochondria and induces fission. Disruption of fission
results in longer, abnormally distributed mitochondrial and peroxisomes. Pathological variants in
DNM1L induce a disorder known as Encephalopathy due to Defective Mitochondrial and Peroxisomal
Fission 1 first described in 2007 in a newborn with microcephaly and optic atrophy [256] . Over time,
other variants expanded the phenotypes with recessive and dominant variants. Isolated optic atrophy
and others with seizures, microcephaly, and global developmental delay were noted in both recessive
and dominant inheritance patterns [257] . Rare recessive variants in MFF have been reported to give rise to
epilepsy, encephalopathy, hypotonia, and Leigh syndrome [258] . The ganglioside-induced differentiation-
associated protein 1 (GDAP1) is located within the outer mitochondrial membrane. This protein promotes
mitochondrial fission through interactions with DMN1L and FIS1 [259] . Variants in GDAP1 produce both
dominant and recessive forms of Charcot-Marie-Tooth disease (CMT), a group of motor or sensory
neuropathy diseases. The recessive forms have reduced fission activity and phenotypically have earlier onset
with a more severe demyelinating subtype of CMT (CMT4A) or a later onset intermediate axonal form
that is less involved (ICMT). In dominant disease, variants in GDAP1 interfere with fusion and induce a
much milder CMT disease (CMT2K). Mfn-1 and -2 are OMM dynamin-like GTPase proteins involved in
fusion [260] . Mfn-2 is involved in tethering mitochondria with ER membranes. Recessive variants in Mfn-2
are the most common cause of axonal induced CMT 2A and produce mtDNA deletions and depletion [261] .

Optic atrophy 1 (OPA1), a mitocholndrial dynamin-like GTPase, is anchored to the IMM within the
intermembrane space and plays a critical role in fusion and mtDNA maintenance. OPA1 anchors mtDNA
to the IMM, organizes ETC supercomplexes and cristae structure, regulates Ca2+ homeostasis, and
[262]
complexes with soluble cytochrome c within the cristae . Depending on location and type of pathological
variant within OPA1, multiple types of disease manifestation occur. The classic autosomal dominant form
of optic atrophy is due to nonsense or frameshift variants (haploinsufficiency), while missense variants
within the GTPase domain produce a dominant negative effect and multisystem disease [263] . Phenotypically,
patients express optic atrophy and retinal ganglion cell layer loss in the classic dominant form, while “plus”
patients, missense variants, display optic neuropathy, sensorineural deafness, ataxia, CPEO, myopathy,
and sensorimotor polyneuropathy. The fusion protein MSTO1 is localized mainly to the OMM. MSTO1
recessive and dominant variants induce abnormalities in mitochondrial fusion and aggregation of
mitochondria at the perinuclear region [264] . Dominant MSTO1 variants have been found in patients with
myopathy, ataxia, optic atrophy, and developmental delay, while recessive variants induce myopathy and
cerebellar ataxia [265,266] . Cytoplasm localization of MSTO1 in some studies suggest the exact location to be
unclear. Sacsin, encoded by SACS is a protein that is thought to disrupt DMN1L function and alter the
balance between fusion and fission [267] . Recessive variants in SACS induces a childhood onset spastic ataxia
disorder, autosomal recessive spastic ataxia of Charevoix-Saguenay. Once thought to be limited to patients
living in Quebec, further findings have identified patients in over 13 countries worldwide. Trak1 is required
for mitofusin-mediated fusion and is localized and interacts with Mfn1 and Mfn2 on the OMM. Trak1 can