The MELAS mutation m.3243A>G alters the expression of mitochondrial tRNA fragments.

08:00 EDT 10th June 2019 | BioPortfolio

Summary of "The MELAS mutation m.3243A>G alters the expression of mitochondrial tRNA fragments."

Recent evidences highlight the importance of mitochondria-nucleus communication for the clinical phenotype of oxidative phosphorylation (OXPHOS) diseases. However, the participation of small non-coding RNAs (sncRNAs) in this communication has been poorly explored. We asked whether OXPHOS dysfunction alters the production of a new class of sncRNAs, mitochondrial tRNA fragments (mt tRFs), and, if so, whether mt tRFs play a physiological role and their accumulation is controlled by the action of mt tRNA modification enzymes. To address these questions, we used a cybrid model of MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes), an OXPHOS disease mostly caused by mutation m.3243A>G in the mitochondrial tRNA gene. High-throughput analysis of small-RNA-Seq data indicated that m.3243A>G significantly changed the expression pattern of mt tRFs. A functional analysis of potential mt tRFs targets (performed under the assumption that these tRFs act as miRNAs) indicated an association with processes that involve the most common affected tissues in MELAS. We present evidences that mt tRFs may be biologically relevant, as one of them (mt i-tRF GluUUC), likely produced by the action of the nuclease Dicer and whose levels are Ago2 dependent, down-regulates the expression of mitochondrial pyruvate carrier 1 (MPC1), promoting the build-up of extracellular lactate. Therefore, our study underpins the idea that retrograde signaling from mitochondria is also mediated by mt tRFs. Finally, we show that accumulation of mt i-tRF GluUUC depends on the modification status of mt tRNAs, which is regulated by the action of stress-responsive miRNAs on mt tRNA modification enzymes.


Journal Details

This article was published in the following journal.

Name: Biochimica et biophysica acta. Molecular cell research
ISSN: 1879-2596


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A dioxygenase and alkylation repair homolog that catalyzes the methylation of 5-carboxymethyl URIDINE to 5-methylcarboxymethyl uridine at the wobble position of the ANTICODON loop in TRANSFER RNA (tRNA) via its methyltransferase domain. It has a preference for tRNA (ARGININE) and tRNA (GLUTAMATE), and does not bind tRNA (LYSINE).

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