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Page 410 Saneto. J Transl Genet Genom 2020;4:384-428 I http://dx.doi.org/10.20517/jtgg.2020.40

RTN4IP1 has a mitochondrial targeted leader sequence, co-localizes with ER at mitochondrial contact sites
and is associated with the outer membrane; however, the exact function is unknown [296] . Biallelic recessive
variants in RTN4IP1 induce early onset optic atrophy with seizures and mild cognitive impairment.

Metabolite solute carriers
Mitochondrial solute carriers, solute carrier family 25 (SLC25), represent a group of 53 proteins required
for transport ions, inorganic metals, vitamins, and substrates into mitochondria that are required for
physiological functioning. All family members possess three specific homologous sequence repeated
domains, each with two transmembrane segments that identify SLC25 genes. Solute transporter proteins
cycle substrates between the cytoplasmic of substrate-binding in the intermembrane space and matrix
delivery and vice versa. Carrier proteins do not have a mitochondrial targeting presequence. They have
an internal targeting signal recognized by the Hsp70-Hsp90 chaperones that allows passage through the
OMM to the IMM. Solute transporter proteins are named SLC25A1-SLC25A53. Eighteen different SLC25A
transporters have been reported to cause disease. A complete review of this subject is beyond the scope of
this article and the reader can refer to a recent review to enlighten the scope of these processes [297] .

Vitamin B1, or thiamine, is a critical cofactor in multiple metabolic processes in the cytosol,
mitochondria, and peroxisome. Free thiamine is transported into the cell using multiple transporters:
two specific transporters, SLC19A2 (thiamine transporter-1) and SLC19A3 (thiamine transporter-2),
with four nonspecific transporters, SLC19A1 (folate transporter), SLC44A4 (human TDP transporter),
SLC22A1 (organic cation transporter 1), and SLC35F3. Once thiamine is transported into the cell,
thiamine is converted into thiamine pyrophosphate (TPP) by thiamine phosphokinase (TPK1), which
is the metabolically active form of thiamine. Active TPP is transported into the mitochondria by the
specific carrier SLC25A19, where it acts as a cofactor of pyruvate dehydrogenase complex, oxoglutarate
dehydrogenase complex, and branched chain 2-oxo acid dehydrogenase complex. Recessive variants can
induce well-defined phenotypes; SLC19A2 induces thiamine responsive megaloblastic anemia or Roger’s
syndrome; SLC19A3 produces biotin thiamine responsive basal ganglia disease and Leigh syndrome; TPK1
causes Leigh syndrome; and SLC25A19 causes Amish microcephaly and episodic encephalopathy with
progressive polyneuropathy [298-300] . All three recessive variants express acute encephalopathy and basal
ganglia changes, with other features of seizures, spasticity, ophthalmoplegia, and peripheral neuropathy.
The importance of diagnosing SLC25A19, SLC19A3, and TPK1 variants is that all three diseases respond to
supplemental thiamine, limiting the disease.

The mitochondrial citrate carrier, SLC25A1, is responsible for the export of citrate to the cytoplasm
needed for lipid, dolichol, ubiquinone, and sterol synthesis. Recessive mutations in SLC25A1 leads to
neonatal-onset encephalopathy, severe muscle weakness, seizures, respiratory compromise, and lack of
psychomotor development [301] . The mitochondrial copper carrier, SLC25A3, is found as two isoforms:
the A form is found in heart and muscle, while the B form is in all the other tissues. The two forms differ
by 13 amino acids. Both isoforms also act as a phosphate carrier [302] . Recessive variants in the SLC25A3-
[303]
isoform A present with muscle hypotonia and hypertrophic cardiomyopathy . A single family has been
shown to have biallelic variants, one in isoform A and the second in isoform B [303] . ANT is a solute carrier
in the IMM and exchanges matrix ATP for cytosolic ADP. There are four tissue-specific isoforms of this
carrier, ANT1-4, each encoded by separate genes. The ANT1 isoform encoded by SLC24A4 is found at
highest levels in the muscle, heart, and brain, and it is found in both dominant and recessive disease [304] .
The dominant forms induce adult onset CPEO and mtDNA deletions, and rarely with childhood onset
with severe respiratory compromise, hypertrophic cardiomyopathy, seizures, and mtDNA depletion and
early death. The recessive form causes childhood/early adult onset of myopathy and cardiomyopathy [305] .
The carrier SLC25A10 transports dicarboxylates and phosphate across the IMM. Inhibition of this function
induces marked reduction in glutathione and a progressive form of epileptic encephalopathy with severe