When a common biological role does not imply common disease outcomes: Disparate pathology linked to human mitochondrial aminoacyl-tRNA synthetases

Abstract

Mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs) are essential components of the mitochondrial translation machinery. The correlation of mitochondrial disorders with mutations in these enzymes has raised the interest of the scientific community over the past several years. Most surprising has been the wide-ranging presentation of clinical manifestations in patients with mt-aaRS mutations, despite the enzymes' common biochemical role. Even among cases where a common physiological system is affected, phenotypes, severity, and age of onset varies depending on which mt-aaRS is mutated. Here, we review work done thus far and propose a categorization of diseases based on tissue specificity that highlights emerging patterns. We further discuss multiple in vitro and in cellulo efforts to characterize the behavior of WT and mutant mt-aaRSs that have shaped hypotheses about the molecular causes of these pathologies. Much remains to do in order to complete our understanding of these proteins. We expect that futher work is likely to result in the discovery of new roles for the mt-aaRSs in addition to their fundamental function in mitochondrial translation, informing the development of treatment strategies and diagnoses.

Keywords: aminoacyl tRNA synthetase; central nervous system (CNS); genetic disease; mitochondria; mutant.

Figure 1.

Schematic representation of a mitochondrion. Mitochondria host numerous metabolic pathways. They are double-membrane organelles, hosting a distinct genome (mtDNA) and translation machinery, dedicated to the synthesis of 13 proteins, all subunits of the respiratory chain complexes (with representatives in all complexes except complex II). All additional proteins required for mtDNA maintenance and expression are encoded in the nucleus, synthesized in the cytosol, and subsequently imported into the mitochondria. This is, for instance, the case for proteins for the mito-ribosome and for mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs). Represented structures are the large (PBD code 4V19) and small (PBD code 5AJ3) subunits of the Sus scrofa mito-ribosome and the human mt-PheRS in complex with tRNA (PBD code 3TUP), mt-TyRS (PDB code 2PID), and mt-AspRS (PDB code 4AH6).

Figure 2.

Canonical tRNAs versus human mitochondrial tRNAs. A, secondary and tertiary structures of canonical tRNAs. The different structural domains are named and colored. The network of tertiary interactions at the origin of the three-dimensional folding is represented by black dashed lines. The nucleotides indicated in black are those conserved in all tRNAs. Y, pyrimidine; R, purine; A, adenosine; C, cytosine; G, guanosine; T, thymine; U, uridine; and Ψ, pseudouridine. Left, cloverleaf consensus secondary structure of canonical tRNAs; middle, two-dimensional representation of tertiary refolding of tRNA; right, crystallographic structure of S. cerevisiae tRNA^Phe (PBD code 1EHZ). B, schematic representations of cloverleaf secondary structures (upper part) and 3D structures (lower part) of human mt-tRNAs. Schematic representations of the general structure of 20 tRNAs (left), of tRNA^Ser(AGY) missing the D-arm (middle), and of tRNA^Ser(UCN) displaying a shorter connector between the acceptor stem and the D-arm (right). Dashed lines correspond to nonstrictly conserved triple interactions. Gray zones highlight domains where variations in the number and type of interactions differ from tRNA to tRNA. This figure is adapted from Ref. .

Figure 3.

Classification of the mt-aaRSs according to the clinical manifestations identified in mt-aaRS–related patients. The mt-aaRSs are shown as graphical representations of their modular organizations. Putative mitochondrial targeting sequences, catalytic domains, and anticodon-binding domains are represented by purple, red, and dark blue bars, respectively. Other system-specific domains are also colored. Data are taken from misynpat.org (33). Disease-associated mutations are represented by colored lollipops, corresponding to homozygous (orange) and compound heterozygous (green) recessive disease-associated missense and nonsense (black) mutations.