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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)2855-2873
Number of pages19
JournalAging
Volume10
Issue number10
DOIs
Publication statusPublished - Oct 1 2018

Keywords

  • Apoptosis
  • Autophagy
  • Bcl-2
  • MitomiRs
  • Senescence

ASJC Scopus subject areas

  • Ageing
  • Cell Biology

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    Giuliani, A., Cirilli, I., Prattichizzo, F., Mensà, E., Fulgenzi, G., Sabbatinelli, J., Graciotti, L., Olivieri, F., Procopio, A. D., Tiano, L., & Rippo, M. R. (2018). The mitomiR/Bcl-2 axis affects mitochondrial function and autophagic vacuole formation in senescent endothelial cells. Aging, 10(10), 2855-2873. https://doi.org/10.18632/aging.101591