Mitochondrial tRNA-Derived Fragments and Their Contribution to Gene Expression Regulation

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.

RetroGREAT signaling: The lessons we learn from yeast

“…71,72 More research is needed to determine the whole plethora of retrograde stimuli in addition to the decrease in mitochondrial potential, free radicals, and a decrease in ATP level. In higher eukaryotes it was reported that calcium concentration, 73 Krebs cycle metabolites, 74 mitochondrial-derived peptides, 45,46 and recently ncRNA (non-coding RNA) 75,76 including mt-tRF (mitochondrial tRNA-derived fragments) 77,78 facilitate signaling to the nucleus in response to mitochondrial damage. It is among the most pressing questions to describe the exact role of the triggers mentioned above in yeast.…”

Context-Dependent Regulation of Gene Expression by Non-Canonical Small RNAs

“…Stress signals can also affect the stability of mitochondrial tRNAs leading to their cleavage and the production of mitochondrial tRFs (mt-tRFs). Several mt-tRFs are produced because of the excessive mitochondrial stress affecting mitochondrial DNA integrity [ 179 ].…”

Small RNA‐seq and clinical evaluation of tRNA‐derived fragments in multiple myeloma: Loss of mitochondrial i‐tRFHisGTG results in patients' poor treatment outcome

“…15,16 Interestingly, a substantial proportion of tRFs arises from mitochondrial tRNAs (mt-tRNAs) and are actively implicated in tumorigenesis and cancer progression, primarily through their role in perturbing translation and mitochondrial metabolism. 17,18 Herein, we have investigated tRF profiles in association with MM and benign disease states (MGUS/sMM), aiming to reveal potential MM-related tRFs of clinical significance.…”

“…tRFs play pivotal roles in regulating gene expression, acting in a miRNA‐like manner and affecting numerous biological processes, including cell proliferation, migration and apoptosis 15,16 . Interestingly, a substantial proportion of tRFs arises from mitochondrial tRNAs (mt‐tRNAs) and are actively implicated in tumorigenesis and cancer progression, primarily through their role in perturbing translation and mitochondrial metabolism 17,18 …”