Modification and aminoacylation of human mitochondrial tRNAs

Mitochondrial tRNAs (mt-tRNAs) are central to energy production by translating essential oxidative phosphorylation subunits. Following transcription, mt-tRNAs undergo diverse processing steps, post-transcriptional modifications, and aminoacylation, which are critical for their functions. In this article, we review how human mt-tRNA-modifying enzymes deposit various post-transcriptional modifications onto mt-tRNAs, encompassing both well-characterized and less-understood marks. We also summarize the principles, peculiarities, and critical roles of mt-tRNA charging and proofreading, and highlight recently uncovered noncanonical functions of mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs). Collectively, these recent findings demonstrate the dynamic regulatory mechanisms of mt-tRNA modification and aminoacylation, the extensive involvement of mt-aaRSs in cellular metabolic pathways, and the promising potential of targeting these enzymes in therapeutics.