Page 172 - Read Online

Page 400 Saneto. J Transl Genet Genom 2020;4:384-428 I http://dx.doi.org/10.20517/jtgg.2020.40

Mitochondrial mt-tRNA and mt-mRNA processing and stabilization
The complete overview of mt-tRNA processing and stabilization is beyond the scope of this article but
can be found in the review by Hallberg and Larsson [167] . As the transcript is synthesized, the mt-tRNAs
are processed first at the 5’ end, and then in a subsequent step at the 3’ end. The 5’ end of the mt-tRNA
is released by the RNase P-complex (RNase P). The RNase P complex is composed of three proteins,
MRRP1, MRRP2, and MRRP3. Two of the RNase P components have a methyltransferase activity and
this subcomplex is first to bind the 5’ end of the mt-tRNA, likely then followed by the MRRP3 protein,
and cleaves the primary transcript at the 5’ end. Alterations in both MRRP1 and MRRP2 have been
shown to cause disease. MRRP1 changes have been described in patients with infantile lactic acidosis,
deafness, and early death [168] . Variants in the MRRP2 subunit induce developmental regression, seizures,
and involuntary movements [169] . The remaining mt-tRNA is then released fully by cleavage at the 3’ end
by RNAase Z (ELAC2). This cleavage releases the mt-tRNA from the mt-mRNA and mt-rRNA within the
long polycistronic transcript. Pathological variants in ELAC2 have been shown to give rise to infantile
hypertrophic cardiomyopathy, global developmental delay, and early death [170] . Rare patients have
expressed abnormal involuntary movements, acanthocytosis, and psychosis and live into adulthood [171] .
PNPase, encoded by PNPT1, is a critical enzyme in polycistronic mtRNA transcript metabolism and
likely import [172] . The range of disease is wide with some patients expressing sensorineural hearing loss,
choreoathetosis, visual loss, and cataracts. Some patients express Leigh syndrome.

Once the mt-tRNA has been excised from the polycistronic mRNA, the released 11 mtDNA-encoded
subunits are clipped. The ND6 mt-mRNA is immediately ready for translation without further processing.
The other subunit mt-mRNAs are polyadenylated performed by mtPAP, a mitochondrial polyA polymerase
encoded by MTPAP. Dysfunctional mtPAP produces range of disease, with a more common presentation
of a progressive spastic ataxia, optic atrophy, and learning difficulties, but some variants also induce an
early infantile death [173,174] . The leucine-rich pentatricopeptide repeat-containing protein (LRPPRC) is found
mainly in the matrix, where it controls mRNA stability [175] . Variants in the LRPPRC gene can produce the
French-Canadian type of Leigh syndrome [176] . The fas-activated serine-threonine kinase (FASTK) family of
proteins are RNA-binding proteins. One of these proteins, fas-activated serine-threonine kinase domain
2 (FASTKD2) is tissue specific, and variants in FASTKD2 have been linked to developmental delay and
myopathy [177] . In some tissues, FASTKD2 is responsible for ND6 messenger RNA and 16S ribosomal RNA
stability [178] . There are three proteins responsible for maturation of the 16S mt-ribosome: MRM1, MRM2,
and RNMTL1. These proteins are responsible for the 2’-O-ribose modification. A MELAS-like syndrome
has been reported with MRM2 variants [179] .

The isolated mt-tRNAs need further modifications, likely due to their poor stability. The inherent instability
of the mt-tRNA creates a hot-spot for disease-causing changes. Indeed, 45 pathological variants and
over 200 variants are thought to be disease related (http://www.mitomap.org/MITOMAP). Two types of
modifications occur in mt-tRNA, structure and codon-anticodon recognition. The order of mt-tRNA
modification is not completely clear. Methylation is critical for obtaining proper cloverleaf structure of the
mt-tRNAs. Early modification of methylation occurs during the 5’ processing and before cleavage at the 3’
end, with the RNase P methyltransferase activity of MRRP1 (also known as TRMT10C) and the gene product
of HSD17B10, MRRP2 [180] . Codon and anticodon recognition occur after 3’ cleavage. There are several
mt-tRNAs that require modifications to stabilize the U-G wobble pairing. Precursor tRNAs are modified
[155]
at the 3’ end by tRNA nucleotydyl transferase 1, which adds a CCA sequence . The methyltransferase
TRMT5 modifies tRNA at position G37 to contribute to the high fidelity of codon recognition in several
mt-tRNAs [181] . The exact mechanism remains unclear, but taurine medication is required for five mt-RNAs,
Trp
Lys
Gln
Glu
tRNA , tRNA , tRNA , tRNA Leu(UUR) , and tRNA . The gene products from MTO1 and GTPBP3 are
intimately responsible for the 5-taurinomethyl group addition of these tRNAs while TRMU catalyzes the
Gln
Glu
thiolation of tRNA , tRNA , and tRNA Lys[182] . Clinically, patients with pathological variants in mt-tRNAs