Aster-B coordinates with Arf1 to regulate mitochondrial cholesterol transport
Objective: Cholesterol plays a pivotal role in mitochondrial steroidogenesis, membrane structure, and respiration. Mitochondrial membranes are intrinsically low in cholesterol content and therefore must be replenished with cholesterol from other subcellular membranes. However, the molecular mechanis...
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Format: | Article |
Language: | English |
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Elsevier
2020-12-01
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Series: | Molecular Metabolism |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877820301290 |
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doaj-ad39d0db05044248aa225aae02d2022d |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
John-Paul Andersen Jun Zhang Haoran Sun Xuyun Liu Jiankang Liu Jia Nie Yuguang Shi |
spellingShingle |
John-Paul Andersen Jun Zhang Haoran Sun Xuyun Liu Jiankang Liu Jia Nie Yuguang Shi Aster-B coordinates with Arf1 to regulate mitochondrial cholesterol transport Molecular Metabolism GRAMD1b Cholesterol transport Mitochondria Arf1 Fatty acids |
author_facet |
John-Paul Andersen Jun Zhang Haoran Sun Xuyun Liu Jiankang Liu Jia Nie Yuguang Shi |
author_sort |
John-Paul Andersen |
title |
Aster-B coordinates with Arf1 to regulate mitochondrial cholesterol transport |
title_short |
Aster-B coordinates with Arf1 to regulate mitochondrial cholesterol transport |
title_full |
Aster-B coordinates with Arf1 to regulate mitochondrial cholesterol transport |
title_fullStr |
Aster-B coordinates with Arf1 to regulate mitochondrial cholesterol transport |
title_full_unstemmed |
Aster-B coordinates with Arf1 to regulate mitochondrial cholesterol transport |
title_sort |
aster-b coordinates with arf1 to regulate mitochondrial cholesterol transport |
publisher |
Elsevier |
series |
Molecular Metabolism |
issn |
2212-8778 |
publishDate |
2020-12-01 |
description |
Objective: Cholesterol plays a pivotal role in mitochondrial steroidogenesis, membrane structure, and respiration. Mitochondrial membranes are intrinsically low in cholesterol content and therefore must be replenished with cholesterol from other subcellular membranes. However, the molecular mechanisms underlying mitochondrial cholesterol transport remains poorly understood. The Aster-B gene encodes a cholesterol binding protein recently implicated in cholesterol trafficking from the plasma membrane to the endoplasmic reticulum (ER). In this study, we investigated the function and underlying mechanism of Aster-B in mediating mitochondrial cholesterol transport. Methods: CRISPR/Cas9 gene editing was carried out to generate cell lines deficient in Aster-B expression. The effect of Aster-B deficiency on mitochondrial cholesterol transport was examined by both confocal imaging analysis and biochemical assays. Deletion mutational analysis was also carried out to identify the function of a putative mitochondrial targeting sequence (MTS) at the N-terminus of Aster-B for its role in targeting Aster-B to mitochondria and in mediating mitochondrial cholesterol trafficking. Results: Ablation of Aster-B impaired cholesterol transport from the ER to mitochondria, leading to a significant decrease in mitochondrial cholesterol content. Aster-B is also required for mitochondrial transport of fatty acids derived from hydrolysis of cholesterol esters. A putative MTS at the N-terminus of Aster-B mediates the mitochondrial cholesterol uptake. Deletion of the MTS or ablation of Arf1 GTPase which is required for mitochondrial translocation of ER proteins prevented mitochondrial cholesterol transport, leading to mitochondrial dysfunction. Conclusions: We identified Aster-B as a key regulator of cholesterol transport from the ER to mitochondria. Aster-B also coordinates mitochondrial cholesterol trafficking with uptake of fatty acids derived from cholesterol esters, implicating the Aster-B protein as a novel regulator of steroidogenesis. |
topic |
GRAMD1b Cholesterol transport Mitochondria Arf1 Fatty acids |
url |
http://www.sciencedirect.com/science/article/pii/S2212877820301290 |
work_keys_str_mv |
AT johnpaulandersen asterbcoordinateswitharf1toregulatemitochondrialcholesteroltransport AT junzhang asterbcoordinateswitharf1toregulatemitochondrialcholesteroltransport AT haoransun asterbcoordinateswitharf1toregulatemitochondrialcholesteroltransport AT xuyunliu asterbcoordinateswitharf1toregulatemitochondrialcholesteroltransport AT jiankangliu asterbcoordinateswitharf1toregulatemitochondrialcholesteroltransport AT jianie asterbcoordinateswitharf1toregulatemitochondrialcholesteroltransport AT yuguangshi asterbcoordinateswitharf1toregulatemitochondrialcholesteroltransport |
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1724401414890848256 |
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doaj-ad39d0db05044248aa225aae02d2022d2020-12-03T04:31:18ZengElsevierMolecular Metabolism2212-87782020-12-0142101055Aster-B coordinates with Arf1 to regulate mitochondrial cholesterol transportJohn-Paul Andersen0Jun Zhang1Haoran Sun2Xuyun Liu3Jiankang Liu4Jia Nie5Yuguang Shi6Sam and Ann Barshop Institute for Longevity and Aging Studies, Department of Pharmacology, University of Texas Health Science Center at San Antonio, Texas Research Park Campus - MC 7755, 15355 Lambda Drive, San Antonio, TX, 78245, USASam and Ann Barshop Institute for Longevity and Aging Studies, Department of Pharmacology, University of Texas Health Science Center at San Antonio, Texas Research Park Campus - MC 7755, 15355 Lambda Drive, San Antonio, TX, 78245, USADepartment of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, PR ChinaSam and Ann Barshop Institute for Longevity and Aging Studies, Department of Pharmacology, University of Texas Health Science Center at San Antonio, Texas Research Park Campus - MC 7755, 15355 Lambda Drive, San Antonio, TX, 78245, USA; Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical, Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, PR ChinaCenter for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical, Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, PR ChinaSam and Ann Barshop Institute for Longevity and Aging Studies, Department of Pharmacology, University of Texas Health Science Center at San Antonio, Texas Research Park Campus - MC 7755, 15355 Lambda Drive, San Antonio, TX, 78245, USASam and Ann Barshop Institute for Longevity and Aging Studies, Department of Pharmacology, University of Texas Health Science Center at San Antonio, Texas Research Park Campus - MC 7755, 15355 Lambda Drive, San Antonio, TX, 78245, USA; Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, PR China; Corresponding author. Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, Texas Research Park Campus - MC 7755, 15355 Lambda Drive, San Antonio, TX, 78245, USA. Fax: +210 562 6150.Objective: Cholesterol plays a pivotal role in mitochondrial steroidogenesis, membrane structure, and respiration. Mitochondrial membranes are intrinsically low in cholesterol content and therefore must be replenished with cholesterol from other subcellular membranes. However, the molecular mechanisms underlying mitochondrial cholesterol transport remains poorly understood. The Aster-B gene encodes a cholesterol binding protein recently implicated in cholesterol trafficking from the plasma membrane to the endoplasmic reticulum (ER). In this study, we investigated the function and underlying mechanism of Aster-B in mediating mitochondrial cholesterol transport. Methods: CRISPR/Cas9 gene editing was carried out to generate cell lines deficient in Aster-B expression. The effect of Aster-B deficiency on mitochondrial cholesterol transport was examined by both confocal imaging analysis and biochemical assays. Deletion mutational analysis was also carried out to identify the function of a putative mitochondrial targeting sequence (MTS) at the N-terminus of Aster-B for its role in targeting Aster-B to mitochondria and in mediating mitochondrial cholesterol trafficking. Results: Ablation of Aster-B impaired cholesterol transport from the ER to mitochondria, leading to a significant decrease in mitochondrial cholesterol content. Aster-B is also required for mitochondrial transport of fatty acids derived from hydrolysis of cholesterol esters. A putative MTS at the N-terminus of Aster-B mediates the mitochondrial cholesterol uptake. Deletion of the MTS or ablation of Arf1 GTPase which is required for mitochondrial translocation of ER proteins prevented mitochondrial cholesterol transport, leading to mitochondrial dysfunction. Conclusions: We identified Aster-B as a key regulator of cholesterol transport from the ER to mitochondria. Aster-B also coordinates mitochondrial cholesterol trafficking with uptake of fatty acids derived from cholesterol esters, implicating the Aster-B protein as a novel regulator of steroidogenesis.http://www.sciencedirect.com/science/article/pii/S2212877820301290GRAMD1bCholesterol transportMitochondriaArf1Fatty acids |