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Saneto. J Transl Genet Genom 2020;4:384-428 I http://dx.doi.org/10.20517/jtgg.2020.40 Page 399

The importance of proper transcription and translation of the 13 mtDNA-derived subunits for proper
functioning is the finding that all 22 mt-tRNAs encoded by mtDNA have pathological variants inducing
disease. There are 45 reported confirmed pathological point variants in MITOMAP (http://www.mitomap.
org/MITOMAP) with over 200 variants reported as possible or likely pathogenic variants. The pathological
variants in mt-tRNA producing disease involve either negative effect on biogenesis and functioning of
tRNAs after their transcription; including processing, post-transcriptional modification, aminoacylation,
association with mt EF-Tu, and/or interactions with mitoribosome during translation [154,155] . To completely
eliminate tRNA function directly, the pathological variant would have to alter one of the anticodon bases
or the discriminatory bases that are critical for codon recognition and aminoacylation, which is a rare
occurrence and likely would lead to incompatibility with life. The majority of variants altered tertiary
structure of the tRNA, efficiency of 3’ processing, and elongation factor binding [155] .

One of the most common mtDNA-encoded disorders is the syndrome, mitochondrial encephalopmyopathy,
lactic acidosis, and stroke-like episodes (MELAS). Over 80% of all patients have a pathological variant m.
Leu
3243A>G in the tRNA gene, MT-TL1 [156,157] . There are at least five other pathological variants in the MT-
TL1 gene as well as other mt-tRNA genes, protein-encoding genes, and large deletions have been described
as inducing MELAS [157] . The invariant clinical criteria for diagnosis are: stroke-like episodes before the age
of 40 years, encephalopathy characterized by seizures and/or dementia, and mitochondrial myopathy, as
evidenced by lactic acidosis and/or ragged red fibers. The diagnosis is confirmed if there are at least two
of the following: (1) normal early psychomotor development; (2) recurrent headaches, and (3) recurrent
vomiting episodes [158] .

Mitochondrial translation
The essential backbone of tRNA and rRNA for protein synthesis or translation, in addition to the 13
mtDNA-encoded subunits in the ETC, are found in the mitochondrial genome, 2 rRNA subunits and 22
tRNAs. There are at least 80 nuclear-encoded proteins required for proper mt-ribosome function [159,160] .
There are at least another 80 nuclear DNA-encoded products needed for translation, mRNA processing
and maturation, and protein synthesis of the 13 ETC subunits [161] . After synthesis in the matrix, proteins are
inserted into the IMM and assembled into the ETC protein complex.

The translation process can be divided into initiation, elongation, termination, and recycling. A full
description is beyond the scope of this paper, but recently reviewed by Ott et al. [162] . Briefly, after the
dissociation of the mitoribosome complex, the process of translation is started by the binding of the
charged fMet-tRNA to the small rRNA subunit. This binding causes the large ribosomal subunit to bind,
the completed monosome is formed, and elongation begins. The elongation process continues until the stop
codon is reached and the completed polypeptide is released. The two ribosomal subunits dissociate and the
mRNA and deacylate mt-tRNA are recycled.

Nine of the 80 nuclear-encoded genes in the mitochondrial ribosomal proteins and one of the two rRNA-
encoded genes have been reported to induce disease: mtRNR1, ERAL1, MRPS7, MRPS16, MRPS22,
MRPS23, MRPS34, MRPL3, MRPL12, and MRPL44 [162-164] . These disorders range from isolated primary
ovarian failure to multisystemic involvement of global development, hepatopathy, cardiomyopathy, kidney
disease, neurosensory hearing loss, and Leigh syndrome. Death can be during infancy or survival can last
multiple decades. When a patient carrying the m. 1555 A>G and m. 1494 C>T variants in the mtDNA-
encoded small ribosome, mtRNR1, is exposed to aminoglycosides, hearing loss occurs; this effect is
profound that even only a single dose results in hearing loss [165,166] . These ecovariants lie silent unless the
patient is exposed to an aminoglycoside antibiotic.