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

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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • DNA, Mitochondrial / genetics
  • Datasets as Topic
  • Down-Regulation
  • Epithelial-Mesenchymal Transition / genetics*
  • Gene Expression Regulation, Developmental
  • Heart / growth & development
  • Heart Failure / genetics*
  • Heart Failure / pathology
  • High-Throughput Nucleotide Sequencing
  • Humans
  • MELAS Syndrome / complications
  • MELAS Syndrome / genetics*
  • MELAS Syndrome / pathology
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Mitochondria / genetics
  • Mitochondria / pathology
  • Muscle, Skeletal / cytology
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Mutation
  • Myocardium / cytology
  • Myocardium / metabolism
  • Myocardium / pathology*
  • Oxidative Phosphorylation
  • RNA, Transfer, Leu / genetics*
  • Sequence Analysis, RNA
  • Signal Transduction / genetics
  • TGF-beta Superfamily Proteins / genetics
  • TGF-beta Superfamily Proteins / metabolism
  • Up-Regulation


  • DNA, Mitochondrial
  • MT-TL1 tRNA, human
  • MicroRNAs
  • RNA, Transfer, Leu
  • TGF-beta Superfamily Proteins