The Multifunctional Sorting Protein PACS-2 Controls Mitophagosome Formation in Human Vascular Smooth Muscle Cells through Mitochondria-ER Contact Sites
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 implicat...
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| Format: | Article |
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MDPI AG
2019-06-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/8/6/638 |
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| author | Manon Moulis Elisa Grousset Julien Faccini Kevin Richetin Gary Thomas Cecile Vindis |
| author_facet | Manon Moulis Elisa Grousset Julien Faccini Kevin Richetin Gary Thomas Cecile Vindis |
| author_sort | Manon Moulis |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T07:47:58Z |
| format | Article |
| id | doaj.art-9426c41154944900b2ff24cc520906c1 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-12T07:47:58Z |
| publishDate | 2019-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-9426c41154944900b2ff24cc520906c12023-09-02T20:49:35ZengMDPI AGCells2073-44092019-06-018663810.3390/cells8060638cells8060638The Multifunctional Sorting Protein PACS-2 Controls Mitophagosome Formation in Human Vascular Smooth Muscle Cells through Mitochondria-ER Contact SitesManon Moulis0Elisa Grousset1Julien Faccini2Kevin Richetin3Gary Thomas4Cecile Vindis5INSERM, UMR 1048, Institute of Metabolic and Cardiovascular Diseases/I2MC, F-31342 Toulouse, FranceINSERM, UMR 1048, Institute of Metabolic and Cardiovascular Diseases/I2MC, F-31342 Toulouse, FranceINSERM, UMR 1048, Institute of Metabolic and Cardiovascular Diseases/I2MC, F-31342 Toulouse, FranceCenter for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, 1005 Lausanne, SwitzerlandDepartment of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USAINSERM, UMR 1048, Institute of Metabolic and Cardiovascular Diseases/I2MC, F-31342 Toulouse, FranceMitochondria-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.https://www.mdpi.com/2073-4409/8/6/638PACS-2mitochondria-associated ER membranes (MAMs)mitochondriamitophagyapoptosisatherosclerosisvascular smooth muscle cell |
| spellingShingle | Manon Moulis Elisa Grousset Julien Faccini Kevin Richetin Gary Thomas Cecile Vindis The Multifunctional Sorting Protein PACS-2 Controls Mitophagosome Formation in Human Vascular Smooth Muscle Cells through Mitochondria-ER Contact Sites Cells PACS-2 mitochondria-associated ER membranes (MAMs) mitochondria mitophagy apoptosis atherosclerosis vascular smooth muscle cell |
| title | The Multifunctional Sorting Protein PACS-2 Controls Mitophagosome Formation in Human Vascular Smooth Muscle Cells through Mitochondria-ER Contact Sites |
| title_full | The Multifunctional Sorting Protein PACS-2 Controls Mitophagosome Formation in Human Vascular Smooth Muscle Cells through Mitochondria-ER Contact Sites |
| title_fullStr | The Multifunctional Sorting Protein PACS-2 Controls Mitophagosome Formation in Human Vascular Smooth Muscle Cells through Mitochondria-ER Contact Sites |
| title_full_unstemmed | The Multifunctional Sorting Protein PACS-2 Controls Mitophagosome Formation in Human Vascular Smooth Muscle Cells through Mitochondria-ER Contact Sites |
| title_short | The Multifunctional Sorting Protein PACS-2 Controls Mitophagosome Formation in Human Vascular Smooth Muscle Cells through Mitochondria-ER Contact Sites |
| title_sort | multifunctional sorting protein pacs 2 controls mitophagosome formation in human vascular smooth muscle cells through mitochondria er contact sites |
| topic | PACS-2 mitochondria-associated ER membranes (MAMs) mitochondria mitophagy apoptosis atherosclerosis vascular smooth muscle cell |
| url | https://www.mdpi.com/2073-4409/8/6/638 |
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