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Page 412 Saneto. J Transl Genet Genom 2020;4:384-428 I http://dx.doi.org/10.20517/jtgg.2020.40

The SLC25A42 carrier is responsible for the importation of coenzyme A across the inner membrane
in exchange for deoxyadenine nucleotides and ADP. Recessive variants in SLC25A42 induce a variety
of clinical features and disease onset, from isolated myopathy to combinations of movement disorders,
encephalopathy, seizures, and developmental regression [247] . Increased iron deposition in the basal ganglia
was reported in the globus pallidi and substantia nigra. Unlike other members of the solute carrier family,
SLC25A46 localizes to the OMM and its precise function remains unknown [324] . SLC25A46 has been shown
to interact with both OPA1 and MFN2 suggesting a direct role in fusion/fission dynamics, but also forms
a complex with the cristae remodeling protein MIC60 [325] . Variants in SLC25A46 express range of disease,
although all patients express optic atrophy and axonal neuropathy. There are patients who also express
Leigh syndrome, ponto-cerebellar hypoplasia type 1, diffuse brain and cerebellar atrophy, or ataxia [324,325] .

Calcium uptake enables the cytosol to communicate and regulate energy demand within the
mitochondrion, resulting in activation of ATP production. Transport occurs through a specialized channel
known as the uniporter located in the IMM. The uniporter complex comprises three transmembrane
components, mitochondrial calcium uniporter (MCU), MCUb, and essential MCU regulator (EMRE), and
two peripheral components of mitochondrial calcium uptake 1 (MICU1) and MICU2 [326] . As calcium levels
rise, the inhibitory effect of MICU1 and MICU2 is removed via a conformational change allowing calcium
entry [327] . Recessive variants in MICU1 produces elevations of creatine kinase with normal lactate levels
and ETC activities, but induce a range of symptoms of muscle weakness, fatigue, cognitive delay, and facial
dysmorphism [328] . Variants in the MICU2 gene have been shown to give rise to severe cognitive impairment,
spasticity, and white matter changes [329] .

The Zrt-Irt-like protein (ZIP) family is encoded by the SLC39A8 gene and is responsible for metal
4+
2+
2+
2+
transport, Mn , Zn , Se , and Co , across plasma membrane or intracellular organelles. Specific recessive
2+
variants in SLC39A8 induce reduced Mn levels in mitochondria, which produces profound developmental
delay, dystonia, failure to thrive, and Leigh syndrome [330] .
The mitochondrial pyruvate carrier (MPC) is a protein complex consisting of two subunits, MPC1 and
MPC2 [331] . There are two recessive variants in MPC1; one results in loss of the MPC complex and the
other with less active MPC complex. The former induces early death with respiratory, cerebral atrophy,
neurological deterioration, and periventricular leukomalacia. The latter produces a milder phenotype of
psychomotor retardation, hypotonia, seizures, peripheral neuropathy, and visual impairment [332] .

Pyruvate dehydrogenase complex
Pyruvate dehydrogenase complex (PDHC) lies in the matrix and catalyzes the rate-limiting step in
the aerobic oxidation of pyruvate to acetyl CoA. This multimeric complex comprises copies of three
enzymatic subunits, namely pyruvate dehydrogenase (E1), dihydrolipoamide transacetylase (E2), and
dihydrolipoamide dehydrogenase (E3), and an E3 binding protein (BP). E1 complex consists of two
alpha and two beta subunits; the gene encoding the E1a subunit, PDHA1, is X-linked and E1b, PDHB is
autosomal located. Activity is regulated by reversible phosphorylation of the E1a subunit that is controlled
by a family of specific PDHC kinases and phosphatases [333] . Recessive variants in all of the subunits; E1a
(PDH1A), E1b (PDHB), E2 (DLAT), E3 (DLD), and E3BP (PDHX) subunits; or PDH phosphatase (PDP1)
induce disease. Clinically, there is a wide range of findings with most patients having multiple symptoms.
The most common finding is developmental delay and hypotonia, but other symptoms can be present
such as seizures, microcephaly, ataxia, facial dysmorphism, optic atrophy, ptosis, involuntary movements,
and spasticity [334] . The X-linked pyruvate dehydrogenase kinase isoenzyme (PDK3) gene is one of the four
isoenzymes that negatively regulate the activity of PDHC by reversible phosphorylation of E1a. Variants in
PDK3 induces an X-linked Charcot-Marie-Tooth neuropathy [335] .