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 Giuliani 1, , Ilenia Cirilli 2, , Francesco Prattichizzo 3, , Emanuela Mensà 1, , Gianluca Fulgenzi 1, 4, , Jacopo Sabbatinelli 1, , Laura Graciotti 1, , Fabiola Olivieri 1, 5, , Antonio Domenico Procopio 1, 5, , Luca Tiano 2, , Maria Rita Rippo 1, ,

  • 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 ;

https://doi.org/10.18632/aging.101591
How to Cite

Copyright: 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.

Abstract

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.

Abbreviations

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.