Research Paper Volume 10, Issue 10 pp 2855—2873

The mitomiR/Bcl-2 axis affects mitochondrial function and autophagic vacuole formation in senescent endothelial cells

Angelica Giuliani1, , Ilenia Cirilli2, , Francesco Prattichizzo3, , Emanuela Mensà1, , Gianluca Fulgenzi1,4, , Jacopo Sabbatinelli1, , Laura Graciotti1, , Fabiola Olivieri1,5, , Antonio Domenico Procopio1,5, , Luca Tiano2, , Maria Rita Rippo1, ,

  • 1 Department of Clinical and Molecular Sciences (DISCLIMO), Università Politecnica delle Marche, Ancona, Italy
  • 2 Department of Life and Environmental Sciences, Università Politecnica delle Marche, Ancona, Italy
  • 3 IRCCS MultiMedica, Milano, Italy
  • 4 Neural Development Section, Mouse Cancer Genetics Program, CCR, NCI, Frederick, MD 21702, USA
  • 5 Center of Clinical Pathology and Innovative Therapy, IRCCS INRCA National Institute, Ancona, Italy

Received: August 8, 2018       Accepted: October 5, 2018       Published: October 21, 2018
How to Cite

Copyright: © 2018 Giuliani et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


During senescence, cells undergo distinctive biochemical and morphological changes and become dysfunctional. MiRNAs are involved in the senescence process and specific miRNAs can localize to mitochondria (mitomiRs). We hypothesized that part of the typical alterations of senescence may depends on mitomiRs deregulation. Therefore, we thoroughly explored the phenotype of human endothelial cells undergoing replicative senescence (sHUVECs) and observed elongated/branched mitochondria, accumulation of autophagic vacuoles (AVs), increased ROS and IL-1β production and reduced expression of Bcl-2 compared to younger cells (yHUVECs). Despite these pro-apoptotic features, sHUVECs are more resistant to serum deprivation, conceivably due to development of pro-survival strategies such as upregulation of Bcl-xL and Survivin. We demonstrate that mitomiR-181a, -34a, and -146a, are overexpressed and localize to mitochondria in sHUVECs compared with yHUVECs and that they: i) down-regulate Bcl-2, ii) induce permeability transition pore opening and activation of caspase-1 and 3, iii) affect sensitivity to apoptosis and iv) promote the conversion of LC3-I to LC3-II. Overall, we document for the first time that some mitomiRs can act as mediators of the multiple but functionally linked biochemical and morphological changes that characterize aging cells and that they can promote different cellular outcomes according to the senescence status of the cell.


ARD: age-related disease; AV: autophagic vacuole; SC: senescent cell; HUVEC: human umbilical vein endothelial cell; LC3: microtubule-associated protein 1A/1B-light chain 3; miRNA: microRNA; mPTP: mitochondrial permeability transition pore; ROS: reactive oxygen species; SA β-Gal: senescence-associated β-Galactosidase; SA-miRs: senescence-associated microRNAs; sHUVECs: senescent HUVECs; yHUVECs: young HUVECs.