Abstract
Mutations in human mitochondrial tRNAs (mt-tRNAs) are responsible for several and sometimes severe clinical phenotypes, classified among mitochondrial diseases. In addition, post-transcriptional modifications of mt-tRNAs in correlation with several stress signals can affect their stability similarly to what has been described for their nuclear-encoded counterparts. Many of the perturbations related to either point mutations or aberrant modifications of mt-tRNAs can lead to specific cleavage and the production of mitochondrial tRNA-derived fragments (mt-tRFs). Although mt-tRFs have been detected in several studies, the exact biogenesis steps and biological role remain, to a great extent, unexplored. Several mt-tRFs are produced because of the excessive oxidative stress which predominantly affects mitochondrial DNA integrity. In addition, mt-tRFs have been detected in various diseases with possible detrimental consequences, but also their production may represent a response mechanism to external stimuli, including infections from pathogens. Finally, specific point mutations on mt-tRNAs have been reported to impact the pool of the produced mt-tRFs and there is growing evidence suggesting that mt-tRFs can be exported and act in the cytoplasm. In this review, we summarize current knowledge on mitochondrial tRNA-deriving fragments and their possible contribution to gene expression regulation.
Highlights
Mitochondria have evolved as the powerhouse of cells and the central nexus for major metabolic pathways that utilize oxygen for ATP production in eukaryotic cells
Due to the dynamic crosstalk with other subcellular compartments and their profound effects on pathophysiology, mitochondria represent a unique field for studying several regulatory circuits that affect gene expression
Based on the central role of mitochondrial tRNAs during mitochondrial translation, the corresponding mitochondrial tRNA-derived fragments (mt-tRFs) could modulate gene expression regulation in a similar way to achieve fine-tuning of the communication with the nucleus
Summary
Mitochondria have evolved as the powerhouse of cells and the central nexus for major metabolic pathways that utilize oxygen for ATP production in eukaryotic cells. It should be noted that it remains debatable whether and which mt-tRNAs are processed either in the mitochondrion or the cytoplasm to generate mt-tRFs. Enzymes that are targeted into mitochondria could affect mt-tRF biogenesis, like RNase ZL/ELAC2, which has been identified as a hotspot for mutations linked with mitochondrial diseases, such as hypertrophic cardiomyopathy and with prostate cancer (Siira et al, 2018; Saoura et al, 2019). The R781H substitution in RNase ZL/ELAC2, which has been linked with prostate cancer and hypertrophic cardiomyopathy, mainly affects mt-tRNA processing while has no major differences on the nuclear pre-tRNA processing (Minagawa et al, 2005; Saoura et al, 2019) This effect could potentially lead to production of differential mt-tRFs levels and a broader effect in gene expression regulation, both inside and outside mitochondria.
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