Research Papers: Autophagy and Cell Death:
Mitophagy acts as a safeguard mechanism against human vascular smooth muscle cell apoptosis induced by atherogenic lipids
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Audrey Swiader1,2,*, Hripsime Nahapetyan1,2,*, Julien Faccini1,2, Romina D’Angelo1,2, Elodie Mucher1,2, Meyer Elbaz1,2, Patricia Boya3 and Cécile Vindis1,2
1 Inserm, UMR-1048, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France
2 Toulouse University Paul Sabatier, Toulouse, France
3 Department of Cellular and Molecular Biology, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain
* Co-first authors
Cécile Vindis, email:
Keywords: human vascular smooth muscle cell, mitophagy, apoptosis, oxidized lipoproteins, atherosclerosis
Received: November 16, 2015 Accepted: April 12, 2016 Published: April 22, 2016
Mitophagy is a critical cellular process that selectively targets damaged mitochondria for autophagosomal degradation both under baseline conditions and in response to stress preventing oxidative damage and cell death. Recent studies have linked alterations in mitochondria function and reduced autophagy with the development of age-related pathologies. However, the significance of mitochondrial autophagy in vessel wall in response to atherogenic lipid stressors is not known. In the present study, we investigated the role of mitophagy on human vascular smooth muscle cells (VSMC) apoptosis induced by oxidized low-density lipoproteins (LDL). We reported for the first time that the engulfment of defective mitochondria by autophagosomes occurred in human VSMC in response to oxidized LDL. The molecular mechanism mediating mitophagy in human VSMC involved dynamin-related protein 1 (Drp1)-mediated mitochondrial fission, accumulation of PTEN-induced putative kinase 1 (PINK1) and the recruitment of the E3 ubiquitin ligase Parkin to mitochondria. Likewise, we found increased voltage-dependent anion channel 1 (VDAC1) and mitofusin 2 (Mnf2) mitochondrial proteins ubiquitination and LC3 association to mitochondria. Using flow cytometry in the presence of lysosomal inhibitors, we showed that PINK1 and Parkin silencing impaired mitophagy flux and enhanced oxidized LDL-induced VSMC apoptosis. In addition, overexpression of PINK1 and Parkin were protective by limiting cell death. Moreover, reduced Bax levels found in VSMC-overexpressing Parkin indicated cross talk among mitophagy and mitochondrial apoptotic signalling pathways. Altogether these data demonstrate that mitophagy is a safeguard mechanism against human VSMC apoptosis induced by atherogenic stressors and highlight mitophagy as a potential target to stabilize atherosclerotic plaque.
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