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

Autores de CIPF

• 

  Salvador Meseguer Llopis

  Autor

• 

  Mª Carmen Navarro González

  Autor

• Magdalena Villarroya Grau

  Autor

• Rachid Boutoual

  Autor

• María Eugenia Armengod González

  Autor

Participantes ajenos a CIPF

• Panadero J
• Sánchez-Alcázar JA

Grupos de Investigación

• Laboratorio de Circuitos Corticales en Salud y Enfermedad

  

  Jefe/a de Grupo

  Pietro Fazzari

Abstract

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, mitochondria] 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(Leu(UUR)) 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 mitochondria] 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.

Keywords

• sncRNAs; miRNAs; Mitochondrial dysfunction; Retrograde signaling; Mitochondrial-tRNA modification; GTPBP3/MTO1/TRMU