Page 173 - Read Online

Saneto. J Transl Genet Genom 2020;4:384-428 I http://dx.doi.org/10.20517/jtgg.2020.40 Page 401

and processing and modification enzymes have expressed liver failure, cardiomyopathy, lactic acidosis,
and, for unclear reasons, a reversible liver disease [Table 3] [181-183] . Other patients have been found to have
hypertension, myoclonic seizures, deafness, and spastic paraparesis.

Aminoacyl-tRNA synthetases (ARS) are specific enzymes involved in translation. There are 20 mt-tRNAs,
and each has to be charged by one of the 19 specific ARSs. These enzymes catalyze a two-step reaction,
where the ARS activates the amino acid with ATP to form an aminoacyl-adenylate and then transfers
the aminoacyl group to the bound tRNA [184] . There are 17 nuclear-encoded ARSs that are specific for mt-
tRNA and 2 (Glycyl- and Lysyl-tRNA synthetases) that are shared with the cytoplasm. One specific mt-
tRNA synthetase complex, GatCAB amino-tRNA amidotransferase complex, has been identified; GLN-
Gln
tRNA is synthesized indirectly via misacylation via transamidation [185] . The GatCAB complex consists
of gene products of QRSL1, GATB, and GATC required for aminoacylation and subsequent protein
translation [186] . Pathological variants in each of these GatCAB subunit genes have been found to induce a
severe cardiomyopathy. Translation begins with N-formyltransferase (MTFMT) using the substrate met-
Met
tRNA and 10-formyl-tetrahydrofolate. Subsequently, binding of a methyl group to the wobble position
Met
of mt-tRNA by NSUN3 to enhance base pairing [187] . Patients with variants in MTFMT and NSUN3 have
been described with microcephaly, developmental delay muscular weakness, and CPEO. All mitochondrial
ARS have been associated with autosomal recessive disease. Disease manifestations range from single
organ to multisystem dysfunction, including Leigh syndrome [39,184] . Single organ disease has been noted
to be isolated to the central nervous system (CNS) with a leukoencephalopathy and lesions in certain
neuronal cell types, and in isolated peripheral neuropathies, distal myopathy, and renal tubulopathy.
Multisystem disease is also noted, including a Leigh syndrome phenotype, Alpers-Huttenlocher syndrome,
Perrault syndrome, myopathy, lactic acidosis, sideroblastic anemia, spastic paresis, atypical Charcot-Marie-
Tooth disease, loss of cognitive ability, ataxia, and endocrinopathies. Why there is isolated single organ
involvement versus multisystemic disease remains unclear.

Mitochondrial RNA translation
The initiation of the translation process begins by the recruitment of the mt-mRNA to the small mt-rRNA
subunit. The initiation factor, mtIRF, then promotes the dissociation of the mitoribosome into two subunits
and prevents premature reassociation with the larger mt-rRNA subunit [188] . Subsequently, the charged
fMET-tRNA binds at the P site of the small mt-rRNA subunit. With the alignment of the start codon
triplet bound to the anti-codon triplet, stabilization the complex occurs and subsequent association of the
larger mt-rRNA subunit is induced. Once this monoribosome is formed, elongation begins. Variants of the
modifiers of translations, elongation, termination, and protein release factors can cause disease. Three of
the many elongation factors, EFTu, EFTs, and EFG1 (products of the nuclear-encoded genes TUFM, TSFM,
and GRM1), are involved in disease. Pathological variants in each of the three genes induced hepatopathy
and encephalopathy [39,189,190] . The protein products of GRM2 and IFG2 function at the termination step of
translation to disassemble the mitoribosome and allow subsequent cycles of protein synthesis [191] . The gene
C12orf65 is a member of the mitochondrial release factor family, the exact properties of the gene product
remain unclear, it but has been shown to cause a diverse phenotype with the key features of optic atrophy,
peripheral neuropathy, and spastic paraparesis [192] .

The mechanisms to enhance translation mt-mRNA are relatively unknown. The translational activator of
cytochrome oxidase subunit 1 (TACO 1) specifically binds mt-Co1 mRNA and is required for translation
of COX1 with association with the ribose [193] . Pathological variants induce Leigh syndrome, optic atrophy,
and dystonia.