The MELAS mutation m.3243A > G promotes reactivation of fetal cardiac genes and an epithelial-mesenchymal transition-like program via dysregulation of miRNAs

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1864

Article

Meseguer, Salvador¹  Panadero, Joaquin²  Navarro-Gonzalez, Carmen¹  Villarroya, Magda¹  Boutoual, Rachid¹  Pietro Comi, Giacomo³  Armengod, M. -Eugenia^1,4 

[1] CIPF, RNA Modificat & Mitochondrial Dis Lab, Carrer Eduardo Primo Yufera 3, Valencia 46012, Spain

[2] Inst Invest Sanitaria La Fe, Unidad Genom, Ave Fernando Abril Martorell,106 Torre A 7a, Valencia 46026, Spain

[3] Univ Milan, Osped Maggiore Policlin, IRCCS Fdn Ca Granda, Dino Ferrari Ctr,Dept Pathophysiol & Transplantat, Via F Sforza 35, I-20122 Milan, Italy

[4] Ctr Invest Biomed Red Enfermedades Raras CIBERER, Node 721, Madrid 28029, Spain

关键词: OXPHOS diseases;    Heteroplasmy;    Hypertrophic cardiomyopathy;    miR-218-5p;    miR-4775;   

DOI  :  10.1016/j.bbadis.2018.06.014

来源: Elsevier

【 摘 要 】

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 tRNA(Leu(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-beta 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.

【 授权许可】

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