Abstract
BackgroundThere 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 methodsHuman 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 (PPARγ) 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.ResultsEctopic 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.ConclusionBased 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.
Highlights
The underlying epigenetic mechanism that governs the reprogramming of somatic cells into a stem-like phenotype is far from clear several recent findings have revealed that mitochondrial maturation and remodelling drives these somatic cells into either a differentiated or dedifferentiated state [1]
Ectopic expression of miR-2909 within human peripheral blood mononuclear cells (PBMCs) resulted in their reprogramming into stem-like phenotype indicated by mitochondrial globular shaped coupled with cristae-poor morphology
Based upon these results we propose that antagonizing transcription factor (AATF) gene-encoded miR-2909 may act as an epigenetic switch for cellular aerobic-glycolysis to ensure de-differentiation
Summary
The underlying epigenetic mechanism that governs the reprogramming of somatic cells into a stem-like phenotype is far from clear several recent findings have revealed that mitochondrial maturation and remodelling drives these somatic cells into either a differentiated or dedifferentiated state [1]. The differentiated cells exhibit globular mitochondrial shape and functionally immature state [1] This phenomenon is paralleled by increased cellular expression of genes coding for mitochondrial uncoupling protein (UCP2) which in turn ensures aerobic glycolysis by shunting pyruvate out of mitochondria leading to increased production of lactate coupled with reduced ATP level [1,2,3,4,5]. 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 expressed genes having ability to sustain their de-differentiation state and survival
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