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Page 408 Saneto. J Transl Genet Genom 2020;4:384-428 I http://dx.doi.org/10.20517/jtgg.2020.40

also interact with Mfn1 and Mfn2 to act as a tethering factor in fusion [268] . Recessive variants have a range
of disorders from isolated hypertonia to patients having fatal encephalopathy, seizures, delayed myelination,
hyperplexia, and refractory status epilepticus [269,270] .

SLC25A46 belongs to the mitochondrial transporter family but is not known to have transport function.
The protein is located on the OMM and whose function is not clearly defined, but interactions with OPA1,
Mfn-1, and Mfn-2 suggests a function in fusion and maintenance of cristae junctions [271] . Variants in
SLC25A46 produce a wide spectrum of clinical features, with optic atrophy and axonal neuropathy shared
by most all patients. Early death has been reported, with Leigh syndrome or ponto-cerebellar hypoplasia.
Other patients present later in life with optic atrophy diffuse brain and cerebellar atrophy [272,273] .

STAT (signal transduction and activation of transcription) proteins are regulators of early response genes
in the nucleus and roles in mitochondrial functions are beginning to be described. One of the STAT
proteins, STAT2, protects cells from viruses by an interferon-dependent mechanism. In response to a
viral infection, STAT2 translocates to the mitochondria, and likely attenuates the cell’s anti-viral response
and suppresses innate immunity [274] . Two patients with homozygous variants within STAT2 were found to
have significantly decreased phosphorylated serine at serine 637 of DMNL1, with impaired fission in the
context of receiving measles, mumps, and rubella vaccination [275] . Patients were healthy until vaccination,
but both soon afterward developed lethargy and lymphadenopathy. Subsequently, one patient developed
episodes of opsoclonus-myoclonus, intractable seizures, and visual impairment. The other developed septic
shock but recovered. The variants in STAT2 are likely ecovariants that lie silent until exposed to specific
environmental stimuli (see above discussion).

The Yeast Vacuolar Protein Sorting-associated Protein (VPS13D) acts downstream of the recruitment of
[276]
the fission factor DMN1L to control fission and clearance by mitophagy . Recessive variants have been
shown to induce a range of diseases from spastic ataxia, chorea, and dystonia to isolated spinocerebellar
ataxia, ranging in onset from infancy to the third decade of life [277] . Two other members of this protein
family, VPS13A and VPS13C, are thought to help tether mitochondria to the ER and act as a lipid
transporter. Recessive variants in VPS13A induce chorea acanthocytosis and in VPS13C early onset
Parkinson disease [278] .

The F-box and Leucine rich repeat protein 4 (FBXL4) is located in the intermembrane space and
recessive FBXL4 variants have been shown to induce severe mtDNA depletion with infant onset
encephalopathy [279,280] . Recently, fibroblast cultures derived from patients demonstrated reduced fusion
rates, but genetically engineered cells with overexpression of FBXL4 were found to express mitochondrial
hyperfusion, suggesting FBXL4 involvement in fusion [280] . An unanswered question of how variants induce
mtDNA depletion remains. Phenotype of biallelic variants consists of early onset, malformation of cortical
development, kidney disease, encephalopathy, skeletal abnormalities, and early death [279-281] .

Extensive mitochondrial damage promotes release of pro-apoptotic factors from the intermembrane
space. Release of the proteins inhibit the cytosolic E3 ubiquitin ligase XIAP and other inhibitors of
apoptosis proteins, one of these proteins is HTRA2/Omi. Recessive variants in HTRA2 induce hypotonia,
extrapyramidal symptoms, lack of psychomotor development, and seizures [282] .

The optic atrophy 3 (OPA3) protein has been localized to the IMM in animal studies and OMM in human
cell culture. Mitochondrial fragmentation found in patient fibroblasts suggests OPA3 is involved in fusion,
but the exact mechanism remains unclear [283] . Loss-of-function recessive and dominant-negative variants
have been described, with phenotypic overlap. Missense biallelic OPA3 variants were first described in an
Iraqi Jewish community to have infantile optic atrophy, movement disorder, spastic paraparesis, ataxia,