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

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 tRNA 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.

Taurine rescues mitochondria-related metabolic impairments in the patient-derived induced pluripotent stem cells and epithelial-mesenchymal transition in the retinal pigment epithelium

“…As has been shown in human RPE samples attached to the choroidal neovascularization extracted by surgery, the EMT of the RPE is involved in AMD pathogenesis [ 17 ]. TGFβ, an inflammatory cytokine that induces EMT in the RPE [ 17 ], was upregulated in the MELAS iPSC-derived RPE, consistent with a previous report that showed augmented TGFB expression caused by the dysregulation of miRNAs in MELAS cybrids [ 58 ]. Mitochondrial dysfunction was reported to change intracellular Ca 2+ signaling and nuclear gene expression in an RPE cell line [ 59 ].…”

miR-218 Affects the ECM Composition and Cell Biomechanical Properties of Glioblastoma Cells

“…Enhanced miR-218 levels also reduced the expression levels of the CRK, RHOA and PTPN1 genes involved in GBM progression [82][83][84]. Our results are supported by data in the literature indicating a decrease in the expression levels of PIK3CA [85], RHOA [86] and STAT3 [45,87] as a consequence of miR-218 overexpression.…”

Roles of the mitochondrial genetics in cancer metastasis: not to be ignored any longer

“…Consistent with this a recent study analyzing the commonly associated MELAS mutation 3243A>G demonstrated that the mutation can promote increased transcription with development and EMT, through modulation of miRNA levels [96]. These results further support a mechanism by which alterations in the mtDNA can alter metastatic susceptibility and tumor progression.…”