title: The ROS-sensitive microRNA-9/9* controls the expression of mitochondrial tRNA-modifying enzymes and is involved in the molecular mechanism of MELAS syndrome.
abstract: Mitochondrial dysfunction activates mitochondria-to-nucleus signaling pathways whose components are mostly unknown. Identification of these components is important to understand the molecular mechanisms underlying mitochondrial diseases and to discover putative therapeutic targets. MELAS syndrome is a rare neurodegenerative disease caused by mutations in mitochondrial (mt) DNA affecting mt-tRNA(Leu(UUR)). Patient and cybrid cells exhibit elevated oxidative stress. Moreover, mutant mt-tRNAs(Leu(UUR)) lack the taurine-containing modification normally present at the wobble uridine (U34) of wild-type mt-tRNA(Leu(UUR)), which is considered an etiology of MELAS. However, the molecular mechanism is still unclear. We found that MELAS cybrids exhibit a significant decrease in the steady-state levels of several mt-tRNA-modification enzymes, which is not due to transcriptional regulation. We demonstrated that oxidative stress mediates an NFkB-dependent induction of microRNA-9/9*, which acts as a post-transcriptional negative regulator of the mt-tRNA-modification enzymes GTPBP3, MTO1 and TRMU. Down-regulation of these enzymes by microRNA-9/9* affects the U34 modification status of non-mutant tRNAs and contributes to the MELAS phenotype. Anti-microRNA-9 treatments of MELAS cybrids reverse the phenotype, whereas miR-9 transfection of wild-type cells mimics the effects of siRNA-mediated down-regulation of GTPBP3, MTO1 and TRMU. Our data represent the first evidence that an mt-DNA disease can directly affect microRNA expression. Moreover, we demonstrate that the modification status of mt-tRNAs is dynamic and that cells respond to stress by modulating the expression of mt-tRNA-modifying enzymes. microRNA-9/9* is a crucial player in mitochondria-to-nucleus signaling as it regulates expression of nuclear genes in response to changes in the functional state of mitochondria.
authors.affiliation: Laboratory of RNA Modification and Mitochondrial Diseases, Centro de Investigación Príncipe Felipe, Valencia 46012, Spain smeseguer@cipf.es marmengod@cipf.es.
authors.forename: Salvador
authors.initials: S
authors.lastname: Meseguer
authors.affiliation: Laboratory of RNA Modification and Mitochondrial Diseases, Centro de Investigación Príncipe Felipe, Valencia 46012, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Martínez-Zamora
authors.affiliation: Hospital Universitari Vall d'Hebron, Institut de Recerca, Universitat Autònoma de Barcelona, Barcelona 08035, Spain Biomedical Research Networking Centre for Rare Diseases (CIBERER) (node U701), Barcelona, Spain and.
authors.forename: Elena
authors.initials: E
authors.lastname: García-Arumí
authors.affiliation: Hospital Universitari Vall d'Hebron, Institut de Recerca, Universitat Autònoma de Barcelona, Barcelona 08035, Spain Biomedical Research Networking Centre for Rare Diseases (CIBERER) (node U701), Barcelona, Spain and.
authors.forename: Antonio L
authors.initials: AL
authors.lastname: Andreu
authors.affiliation: Laboratory of RNA Modification and Mitochondrial Diseases, Centro de Investigación Príncipe Felipe, Valencia 46012, Spain CIBERER (node U721), Valencia, Spain smeseguer@cipf.es marmengod@cipf.es.
authors.forename: M-Eugenia
authors.initials: ME
authors.lastname: Armengod
mesh_terms: D002352:Carrier Proteins / Q000235:genetics*; D002467:Cell Nucleus / Q000235:genetics; D002478:Cells, Cultured; D015536:Down-Regulation; D019204:GTP-Binding Proteins / Q000235:genetics*; D006801:Humans; D017241:MELAS Syndrome / Q000235:genetics*; D035683:MicroRNAs / Q000378:metabolism*; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics*; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress; D012313:RNA / Q000378:metabolism; D000077278:RNA, Mitochondrial; D012356:RNA, Transfer, Leu / Q000378:metabolism; D016601:RNA-Binding Proteins; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D012359:tRNA Methyltransferases / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; C541874:MIRN92 microRNA, human; C492006:MTO1 protein, human; D035683:MicroRNAs; D024101:Mitochondrial Proteins; D016328:NF-kappa B; D000077278:RNA, Mitochondrial; D012356:RNA, Transfer, Leu; D016601:RNA-Binding Proteins; D017382:Reactive Oxygen Species; D012313:RNA; D012359:tRNA Methyltransferases; C496706:TRMU protein, human; D019204:GTP-Binding Proteins; C498989:GTPBP3 protein, human