Pathogenic Implications of Human Mitochondrial Aminoacyl-tRNA Synthetases

Abstract

Mitochondria are considered as the powerhouse of eukaryotic cells. They host several central metabolic processes fueling the oxidative phosphorylation pathway (OXPHOS) that produces ATP from its precursors ADP and inorganic phosphate Pi (PPi). The respiratory chain complexes responsible for the OXPHOS pathway are formed from complementary sets of protein subunits encoded by the nuclear genome and the mitochondrial genome, respectively. The expression of the mitochondrial genome requires a specific and fully active translation machinery from which aminoacyl-tRNA synthetases (aaRSs) are key actors. Whilst the macromolecules involved in mammalian mitochondrial translation have been under investigation for many years, there has been an explosion of interest in human mitochondrial aaRSs (mt-aaRSs) since the discovery of a large (and growing) number of mutations in these genes that are linked to a variety of neurodegenerative disorders. Herein we will review the present knowledge on mt-aaRSs in terms of their biogenesis, their connection to mitochondrial respiration, i.e., the respiratory chain (RC) complexes, and to the mitochondrial translation machinery. The pathology-related mutations detected so far are described, with special attention given to their impact on mt-aaRSs biogenesis, functioning, and/or subsequent activities. The collected data to date shed light on the diverse routes that are linking primary molecular possible impact of a mutation to its phenotypic expression. It is envisioned that a variety of mechanisms, inside and outside the translation machinery, would play a role on the heterogeneous manifestations of mitochondrial disorders.

Transfer RNA and human disease

“…Pathological mutations have been identified in 10 of the genes encoding mt-ARSs (Schwenzer et al, 2013). The first of these was identified in the DARS2 gene, which encodes mitochondrial aspartyl-tRNA synthetase (Scheper et al, 2007).…”

“…Mutations in the canonical tRNA partner, aminoacyl tRNA-synthetases (ARSs), were first identified as causative agents of Charcot-Marie-Tooth in 2003 (Antonellis et al, 2003). The subject of ARSs and diseases has also received attention, with a number of useful recent reviews addressing various issues (Kim et al, 2011; Guo and Schimmel, 2013; Jia et al, 2013; Konovalova and Tyynismaa, 2013; Schwenzer et al, 2013; Diodato et al, 2014). A major question yet to be addressed is the localization of translation in neural cells, and how tRNA may be trafficked to ribosomes in distant regions (e.g., long axons and synapses in neurons) of the cell.…”

Biochemical Characterization of the Lysine Acetylation of Tyrosyl‐tRNA Synthetase in Escherichia coli

“…[1] Besides this classic function, aaRSs are also involved in a variety of biological processes, such as RNA splicing, translational and transcriptional regulation, signaling transduction, and cell cycles. [2] Over the past decade, aaRSs have attracted more and more attention due to their association with diseases [3] and applications in genetic-code-expansion strategies. [4] …”

Novel mutations in KARS cause hypertrophic cardiomyopathy and combined mitochondrial respiratory chain defect

“…Encephalopathy is the most common phenotype associated with mutations in mt-ARSs, but other clinical presentations include myopathy, cardiomyopathy, tubulopathy and hearing loss (12,13). Interestingly, in our patient the muscle biopsy showed a marked COX reduction in the striatal muscle, while in the same tissue the capillary walls were normally stained together with the larger intramuscular vessels that similarly showed mitochondrial proliferation.…”