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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.
This article was published in the following journal.
Name: Biochimica et biophysica acta. Molecular cell research
The disease entity mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is characterized by an early onset of stroke-like episodes. MELAS is the most dominant subtype of ...
Mitochondrial mutations are associated with a wide spectrum of clinical abnormalities. More than half of these mutations are distributed in the 22 mitochondrial tRNA genes, including tRNA. In particul...
Transfer RNAs (tRNAs) are a major class of noncoding RNA. Stress-induced cleavage of tRNA is highly conserved and results in tRNA fragments. Here we find specific tRNA fragments in plasma are associat...
We present a 14-year-old girl with loss of motor functions, tetraplegia, epilepsy and nystagmus, caused by a novel heteroplasmic m.641A>T transition in an evolutionary conserved region of mitochondria...
Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) are thought to be rarely accompanied by macroangiopathy. We reported a case of MELAS that presented right distal internal...
The m.3243A>G mutation is the most frequent cause of mitochondrial disease in adults, for which currently no therapy is available and treatment is solely supportive. Since both malnutritio...
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Patients with the MELAS syndrome experience devastating mental impairment. This study will evaluate the effectiveness of the drug dichloroacetate (DCA) to reduce the symptoms of MELAS.
Mitochondrial Diseases are rare, progressive, multi-system, often-early fatal disorders affecting both children and adults. KH176 is a novel chemical entity currently under development for...
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).
A modified nucleoside which is present in the first position of the anticodon of tRNA-tyrosine, tRNA-histidine, tRNA-asparagine and tRNA-aspartic acid of many organisms. It is believed to play a role in the regulatory function of tRNA. Nucleoside Q can be further modified to nucleoside Q*, which has a mannose or galactose moiety linked to position 4 of its cyclopentenediol moiety.
A mutation that results in an increase in a gene's activity or in acquiring a new molecular function or a new pattern of gene expression.
A mitochondrial uncoupling protein that is expressed in many tissues and exhibits the greatest expression in SKELETAL MUSCLE. It regulates mitochondrial ATP production and the generation of REACTIVE OXYGEN SPECIES.
A complex of polyene antibiotics obtained from Streptomyces filipinensis. Filipin III alters membrane function by interfering with membrane sterols, inhibits mitochondrial respiration, and is proposed as an antifungal agent. Filipins I, II, and IV are less important.
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