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Biochim Biophys Acta Mol Basis Dis. 2018 Sep;1864(9 Pt B):3022-3037. doi: 10.1016/j.bbadis.2018.06.014. Epub 2018 Jun 19.

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

Author information

1
RNA Modification and Mitochondrial Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), Carrer d'Eduardo Primo Yúfera 3, Valencia 46012, Spain. Electronic address: smeseguer@cipf.es.
2
Unidad de Genómica, Instituto de Investigación Sanitaria La Fe, Avenida Fernando Abril Martorell, 106 Torre A 7ª planta, Valencia 46026, Spain. Electronic address: joaquin_panadero@iislafe.es.
3
RNA Modification and Mitochondrial Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), Carrer d'Eduardo Primo Yúfera 3, Valencia 46012, Spain. Electronic address: cnavarrog@cipf.es.
4
RNA Modification and Mitochondrial Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), Carrer d'Eduardo Primo Yúfera 3, Valencia 46012, Spain. Electronic address: mvillarroya@cipf.es.
5
RNA Modification and Mitochondrial Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), Carrer d'Eduardo Primo Yúfera 3, Valencia 46012, Spain. Electronic address: rboutoual@cipf.es.
6
Dino Ferrari Centre, Department of Pathophysiology and Transplantation (DEPT), University of Milan, I.R.C.C.S. Foundation Ca' Granda, Ospedale Maggiore Policlinico, via F. Sforza 35, 20122 Milan, Italy. Electronic address: giacomo.comi@unimi.it.
7
RNA Modification and Mitochondrial Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), Carrer d'Eduardo Primo Yúfera 3, Valencia 46012, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) node 721, Madrid 28029, Spain. Electronic address: marmengod@cipf.es.

Abstract

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.

KEYWORDS:

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

PMID:
29928977
DOI:
10.1016/j.bbadis.2018.06.014
[Indexed for MEDLINE]
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