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The Multifunctional Sorting Protein PACS-2 Controls Mitophagosome Formation in Human Vascular Smooth Muscle Cells through Mitochondria-ER Contact Sites

Moulis, Manon and Grousset, Elisa and Faccini, Julien and Richetin, Kevin and Thomas, Gary and Vindis, Cecile (2019) The Multifunctional Sorting Protein PACS-2 Controls Mitophagosome Formation in Human Vascular Smooth Muscle Cells through Mitochondria-ER Contact Sites. Cells, 8 (6). p. 638. ISSN 2073-4409

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Abstract

Mitochondria-associated ER membranes (MAMs) are crucial for lipid transport and synthesis, calcium exchange, and mitochondrial functions, and they also act as signaling platforms. These contact sites also play a critical role in the decision between autophagy and apoptosis with far reaching implications for cell fate. Vascular smooth muscle cell (VSMC) apoptosis accelerates atherogenesis and the progression of advanced lesions, leading to atherosclerotic plaque vulnerability and medial degeneration. Though the successful autophagy of damaged mitochondria promotes VSMC survival against pro-apoptotic atherogenic stressors, it is unknown whether MAMs are involved in VSMC mitophagy processes. Here, we investigated the role of the multifunctional MAM protein phosphofurin acidic cluster sorting protein 2 (PACS-2) in regulating VSMC survival following a challenge by atherogenic lipids. Using high-resolution confocal microscopy and proximity ligation assays, we found an increase in MAM contacts as in PACS-2-associated MAMs upon stimulation with atherogenic lipids. Correspondingly, the disruption of MAM contacts by PACS-2 knockdown impaired mitophagosome formation and mitophagy, thus potentiating VSMC apoptosis. In conclusion, our data shed new light on the significance of the MAM modulatory protein PACS-2 in vascular cell physiopathology and suggest MAMs may be a new target to modulate VSMC fate and favor atherosclerotic plaque stability.

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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Moulis, Manon
Grousset, Elisa
Faccini, Julien
Richetin, Kevin
Thomas, Garythomasg@pitt.eduthomasg
Vindis, Cecile
Centers: Other Centers, Institutes, Offices, or Units > Hillman Cancer Center
Date: 25 June 2019
Date Type: Publication
Journal or Publication Title: Cells
Volume: 8
Number: 6
Publisher: MDPI AG
Page Range: p. 638
DOI or Unique Handle: 10.3390/cells8060638
Schools and Programs: School of Medicine > Microbiology and Molecular Genetics
Refereed: Yes
Uncontrolled Keywords: PACS-2, mitochondria-associated ER membranes (MAMs), mitochondria, mitophagy, apoptosis, atherosclerosis, vascular smooth muscle cell
ISSN: 2073-4409
Official URL: http://dx.doi.org/10.3390/cells8060638
Funders: l’Institut National de la Santé et de la Recherche Médicale, la Fondation de France, IDEX Toulouse, la Fédération Française de Cardiologie, National Institute of Health
Article Type: Research Article
Date Deposited: 29 Jun 2021 18:46
Last Modified: 29 Jun 2021 18:46
URI: http://d-scholarship.pitt.edu/id/eprint/41306

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