Role of inflamma-mitomiRs miR-146a, miR-181a and miR-34a in regulating mitochondrial dysfunction during replicative senescence of human endothelial cells

The aging process is characterized by a drastic metabolic change, intimately associated with impaired mitochondrial functions and homeostasis: alteration in autophagic clearance and apoptotic rates, oxidative stress and an inflammatory and secretory phenotype (SASP). Current research suggests that some microRNAs can play a direct role in regulating mitochondrial activity (mitomiRs). Ingenuity Pathway Analysis of mitomiRs targets has disclosed that miR-146a, miR-34a and miR-181a are closely linked to each other and to Bcl-2 family linking them to important cell functions (proliferation, death, survival, maintenance) and age-related diseases. We validated this bio-informatic analysis in human senescent endothelial cells (HUVEC) compared to young cell. Selected mitomiRs were up-regulated in senescent cells while a decreased in Bcl-2 protein expression was observed as well as permeability transition pore opening. Transfection of these miRs in young cells produced similar effects at Bcl-2 level and PTP opening, demonstrating a direct link between this miRNA set and mitochondrial dysfunction in senescent cells. Due to Bcl-2 role as metabolic sensors/messengers involved in apoptosis, autophagy and anti-oxidative pathways, the proposed set of regulatory miRs represent an intriguing novel mechanism controlling mitochondrial function and dysfunction during cellular aging.