Human cellular mitochondrial remodelling is governed by miR-2909 RNomics

Abstract

Background There exists a general recognition of the fact that mitochondrial remodelling as a result of aerobic glycolysis ensures human somatic cells to revert to a more primitive-form exhibiting stem-like phenotype. The present study is an attempt to demonstrate that miR-2909 RNomics within human peripheral blood mononuclear cells (PBMCs) has the inherent capacity to re-program these cells to exhibit mitochondrial remodelling paralleled by aerobic glycolysis together with intracellular lipid inclusions. Such re-programmed PBMCs also expressed genes having ability to sustain their de-differentiation state and survival. Material and methods Human PBMCs were programed to ectopically express miR-2909. Expression levels of genes including glucose transporter-1 (Glut-1), hexokinase (HK), hypoxia inducia factor-1 (HIF-1α), c-Myc, p53,mechanistic target of rapamycin complex (mTORC1), polycombcomplex protein (Bmi-1), Notch,Nanog,Tie-2, Oct-4,CD59, p53, CD34, B-cell lymphoma-2 (Bcl2),sterol regulatory element-binding protein2 (SREBP2), peroxisome proliferator-activated receptor gamma (PPARα) nuclear respiratory factor 1 (NRF1), mitochondrial transcription factor A (Tfam), peroxisome proliferator-activated receptor gamma coactivator 1- alpha (PGC1α) within miR-2909 expression vector transfected human PBMCs as well as PBMCs transfected with control vector containing scrambled sequence after 48h post-transfection using RT-qPCR and cellular ultrastructural features induced by miR-2909 ectopic expression were observed using transmission electron microscopy and morphometric analysis of an electron micrograph. Results Ectopic expression of miR-2909 within human PBMCs resulted in their reprogramming into stem-like phenotype indicated by mitochondrial globular shaped coupled with cristae-poor morphology. Nuclear to cytoplasmic ratio (N/C), quantification of ATP levels, GSSG/GSH ratio, mitochondrial cytochrome c oxidase activity, secreted lactate concentrations, activity of antioxidant enzymes, levels of esterified cholesterol and triglycerides and flow-cytometric detection of apoptosis confirmed the compromised nature of mitochondrial function induced by ectopic miR-2909 expression in human PBMCs. Conclusion Based upon these results we propose that AATF gene-encoded miR-2909 may act as an epigenetic switch for cellular aerobic-glycolysis to ensure de-differentiation.