The molecular pathology of pathogenic mitochondrial tRNA variants

Abstract

Mitochondrial diseases are clinically and genetically heterogeneous disorders, caused by pathogenic variants in either the nuclear or mitochondrial genome. This heterogeneity is particularly striking for disease caused by variants in mitochondrial DNA-encoded tRNA (mt-tRNA) genes, posing challenges for both the treatment of patients and understanding the molecular pathology. In this review, we consider disease caused by the two most common pathogenic mt-tRNA variants: m.3243A>G (within MT-TL1, encoding mt-tRNA^Leu(UUR) ) and m.8344A>G (within MT-TK, encoding mt-tRNA^Lys ), which together account for the vast majority of all mt-tRNA-related disease. We compare and contrast the clinical disease they are associated with, as well as their molecular pathologies, and consider what is known about the likely molecular mechanisms of disease. Finally, we discuss the role of mitochondrial-nuclear crosstalk in the manifestation of mt-tRNA-associated disease and how research in this area not only has the potential to uncover molecular mechanisms responsible for the vast clinical heterogeneity associated with these variants but also pave the way to develop treatment options for these devastating diseases.

Keywords: MELAS; MERRF; heteroplasmy; m.3243A>G; m.8344A>G; mitochondrial DNA; mitochondrial disease; mitochondrial tRNA.

Fig. 1

Mitochondrial tRNAs are encoded by the human mitochondrial genome. (A) Schematic representation of the double‐stranded circular human mitochondrial DNA (16.6 kb). The outer circle represents the guanine‐rich heavy strand, which is transcribed from heavy strand promoters 1 and 2 (HSPs), and the inner circle represents the cytosine‐rich light strand, transcribed from the light‐strand promoter (LSP). Thirteen protein‐coding genes encode essential components of the respiratory chain: seven complex I (green; MT‐ND1 to MT‐ND6 and MT‐ND4L); one complex III (purple; MT‐CYB); three complex IV (yellow; MT‐CO1 to MT‐CO3); and two mitochondrial ATP synthase (blue; MT‐ATP6 and MT‐ATP8) subunits. The mitochondrial genome also encodes all of the RNA species required for translation of these polypeptides: MT‐RNR1 and MT‐RNR2 encode mitochondrial 12S and 16S rRNAs (red), and 22 genes encoding mt‐tRNA molecules are distributed throughout the genome (grey bars; mt‐tRNA molecules illustrated as clover‐leaf structures with three letter amino acid codes). The two pathogenic variants discussed in this review, m.3243A>G and m.8344A>G, are found within the genes for mt‐tRNA^Leu(UUR) (Leu‐1) and mt‐tRNA^Lys (Lys), which are highlighted in red. (B) Schematic depicting the secondary structure of mitochondrial mt‐tRNA^Leu(UUR) and mt‐tRNA^Lys highlighting the position of m.3243A>G and m.8344A>G (red). Specific RNA modifications and their responsible ‘writer’ enzymes are colour‐coded. Abbreviations for modified nucleosides are as follows: m1A (1‐methyladenosine), m1G (1‐methylguanosine), m2G (N2‐methylguanosine), m5C (5‐methylcytidine), τm5U (5‐taurinomethyluridine), τm5s2U (5‐taurinomethyl‐2‐thiouridine), t6A (N6‐threonylcarbamoyladenosine), Ψ (pseudouridine).

Fig. 2

Comparison of the phenotypic features of m.3243A>G and m.8344A>G‐related disease. For m.8344A>G, phenotypic frequencies (at last evaluation) were obtained from Refs [95, 97]. For m.3243A>G, frequencies were obtained from Refs [44, 50, 51, 52, 65]. Phenotypes are grouped into neurological (purple), muscle‐related (red) and others (light blue) and ordered by frequency in m.3243A>G patients. Stroke‐like episodes, cognitive impairment, diabetes and gut dysmotility are notably higher in frequency in m.3243A>G patients, whereas ataxia, psychiatric features, myoclonus and myopathy/exercise intolerance are higher in m.8344A>G patients. Lipomas are a noticeable feature of m.8344A>G but not m.3243A>G‐related disease. For phenotypes where more than one estimate of frequency is reported in the literature, the highest estimate is shown in a lighter shade, with the lowest estimate in a darker shade, thus depicting an estimated range.