Opinion
Recent Advances in Mitochondrial Aminoacyl-tRNA Synthetases and Disease

https://doi.org/10.1016/j.molmed.2017.06.002Get rights and content
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Mutations in nucleus-encoded mt-aaRSs impact on tissues with high energy demand, notably the CNS.

Disease-associated mutations occur at positions rarely conserved in phylogeny, but some occur at positions that are highly conserved in mammals.

These observations point to complex molecular origins with either direct and/or indirect effects on the efficiency of mitochondrial translation and/or alternative functions played by mt-aaRSs.

We propose that the pleiotropy and tissue-specificity of these disease-associated mutations reflect the integration of mitochondrial translation processes within cellular homeostasis; these may occur through specific crosstalk between the cellular program and cellular energy demands, especially in neuronal cells.

Among the multiple communication pathways between mitochondria and the nucleus, the mitochondrial unfolded protein response may play a role in the integrated response.

Dysfunctions in mitochondria – the powerhouses of the cell – lead to several human pathologies. Because mitochondria integrate nuclear and mitochondrial genetic systems, they are richly intertwined with cellular activities. The nucleus-encoded mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs) are key components of the mitochondrial translation apparatus. Mutations in these enzymes predominantly affect the central nervous system (CNS) but also target other organs. Comparable mutations in mt-aaRSs can lead to vastly diverse diseases, occurring at different stages in life, and within different tissues; this represents a confounding issue. With newer information available, we propose that the pleiotropy and tissue-specificity of mt-aaRS-associated diseases result from the molecular integration of mitochondrial translation events within the cell; namely, through specific crosstalk between the cellular program and the energy demands of the cell. We place particular focus on neuronal cells.

Keywords

mitochondrial disease
mitochondrial translation
aminoacyl-tRNA synthetase
central nervous system
moonlighting proteins
unfolded protein response

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