The MELAS mutation m.3243AG promotes reactivation of fetal cardiac genes and an epithelial-mesenchymal transition-like program via dysregulation of miRNAs
Autor: | Carmen Navarro-González, M-Eugenia Armengod, Rachid Boutoual, Magda Villarroya, Salvador Meseguer, Giacomo P. Comi, Joaquin Panadero |
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Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Mitochondrial encephalomyopathy Mitochondrial DNA RHOA Epithelial-Mesenchymal Transition RNA Transfer Leu Mutant Datasets as Topic Down-Regulation medicine.disease_cause DNA Mitochondrial Oxidative Phosphorylation 03 medical and health sciences Cell Line Tumor medicine MELAS Syndrome Humans Muscle Skeletal Molecular Biology Heart Failure Mutation biology Sequence Analysis RNA Myocardium Skeletal muscle Gene Expression Regulation Developmental High-Throughput Nucleotide Sequencing Heart medicine.disease Heteroplasmy Mitochondria TGF-beta Superfamily Proteins Up-Regulation MicroRNAs 030104 developmental biology medicine.anatomical_structure Lactic acidosis biology.protein Cancer research Molecular Medicine Signal Transduction |
Zdroj: | Biochimica et biophysica acta. Molecular basis of disease. 1864(9 Pt) |
ISSN: | 0925-4439 |
Popis: | The pathomechanisms underlying oxidative phosphorylation (OXPHOS) diseases are not well-understood, but they involve maladaptive changes in mitochondria-nucleus communication. Many studies on the mitochondria-nucleus cross-talk triggered by mitochondrial dysfunction have focused on the role played by regulatory proteins, while the participation of miRNAs remains poorly explored. MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) is mostly caused by mutation m.3243A>G in mitochondrial tRNALeu(UUR) gene. Adverse cardiac and neurological events are the commonest causes of early death in m.3243A>G patients. Notably, the incidence of major clinical features associated with this mutation has been correlated to the level of m.3243A>G mutant mitochondrial DNA (heteroplasmy) in skeletal muscle. In this work, we used a transmitochondrial cybrid model of MELAS (100% m.3243A>G mutant mitochondrial DNA) to investigate the participation of miRNAs in the mitochondria-nucleus cross-talk associated with OXPHOS dysfunction. High-throughput analysis of small-RNA-Seq data indicated that expression of 246 miRNAs was significantly altered in MELAS cybrids. Validation of selected miRNAs, including miR-4775 and miR-218-5p, in patient muscle samples revealed miRNAs whose expression declined with high levels of mutant heteroplasmy. We show that miR-218-5p and miR-4775 are direct regulators of fetal cardiac genes such as NODAL, RHOA, ISL1 and RXRB, which are up-regulated in MELAS cybrids and in patient muscle samples with heteroplasmy above 60%. Our data clearly indicate that TGF-β superfamily signaling and an epithelial-mesenchymal transition-like program are activated in MELAS cybrids, and suggest that down-regulation of miRNAs regulating fetal cardiac genes is a risk marker of heart failure in patients with OXPHOS diseases. |
Databáze: | OpenAIRE |
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