Mic19 depletion impairs endoplasmic reticulum-mitochondrial contacts and mitochondrial lipid metabolism and triggers liver disease
Abstract Endoplasmic reticulum (ER)-mitochondria contacts are critical for the regulation of lipid transport, synthesis, and metabolism. However, the molecular mechanism and physiological function of endoplasmic reticulum-mitochondrial contacts remain unclear. Here, we show that Mic19, a key subunit...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-44057-6 |
| _version_ | 1797363105596964864 |
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| author | Jun Dong Li Chen Fei Ye Junhui Tang Bing Liu Jiacheng Lin Pang-Hu Zhou Bin Lu Min Wu Jia-Hong Lu Jing-Jing He Simone Engelender Qingtao Meng Zhiyin Song He He |
| author_facet | Jun Dong Li Chen Fei Ye Junhui Tang Bing Liu Jiacheng Lin Pang-Hu Zhou Bin Lu Min Wu Jia-Hong Lu Jing-Jing He Simone Engelender Qingtao Meng Zhiyin Song He He |
| author_sort | Jun Dong |
| collection | DOAJ |
| description | Abstract Endoplasmic reticulum (ER)-mitochondria contacts are critical for the regulation of lipid transport, synthesis, and metabolism. However, the molecular mechanism and physiological function of endoplasmic reticulum-mitochondrial contacts remain unclear. Here, we show that Mic19, a key subunit of MICOS (mitochondrial contact site and cristae organizing system) complex, regulates ER-mitochondria contacts by the EMC2-SLC25A46-Mic19 axis. Mic19 liver specific knockout (LKO) leads to the reduction of ER-mitochondrial contacts, mitochondrial lipid metabolism disorder, disorganization of mitochondrial cristae and mitochondrial unfolded protein stress response in mouse hepatocytes, impairing liver mitochondrial fatty acid β-oxidation and lipid metabolism, which may spontaneously trigger nonalcoholic steatohepatitis (NASH) and liver fibrosis in mice. Whereas, the re-expression of Mic19 in Mic19 LKO hepatocytes blocks the development of liver disease in mice. In addition, Mic19 overexpression suppresses MCD-induced fatty liver disease. Thus, our findings uncover the EMC2-SLC25A46-Mic19 axis as a pathway regulating ER-mitochondria contacts, and reveal that impairment of ER-mitochondria contacts may be a mechanism associated with the development of NASH and liver fibrosis. |
| first_indexed | 2024-03-08T16:16:31Z |
| format | Article |
| id | doaj.art-9ce0791913fe4ff9aa6525cb89bbb6a4 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-08T16:16:31Z |
| publishDate | 2024-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-9ce0791913fe4ff9aa6525cb89bbb6a42024-01-07T12:34:13ZengNature PortfolioNature Communications2041-17232024-01-0115111610.1038/s41467-023-44057-6Mic19 depletion impairs endoplasmic reticulum-mitochondrial contacts and mitochondrial lipid metabolism and triggers liver diseaseJun Dong0Li Chen1Fei Ye2Junhui Tang3Bing Liu4Jiacheng Lin5Pang-Hu Zhou6Bin Lu7Min Wu8Jia-Hong Lu9Jing-Jing He10Simone Engelender11Qingtao Meng12Zhiyin Song13He He14College of Life Sciences, TaiKang Center for Life and Medical Sciences, Frontier Science Center for Immunology and Metabolism, Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan UniversityCollege of Life Sciences, TaiKang Center for Life and Medical Sciences, Frontier Science Center for Immunology and Metabolism, Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan UniversityCollege of Life Sciences, TaiKang Center for Life and Medical Sciences, Frontier Science Center for Immunology and Metabolism, Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan UniversityCollege of Life Sciences, TaiKang Center for Life and Medical Sciences, Frontier Science Center for Immunology and Metabolism, Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan UniversityCollege of Life Sciences, TaiKang Center for Life and Medical Sciences, Frontier Science Center for Immunology and Metabolism, Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan UniversityCollege of Life Sciences, TaiKang Center for Life and Medical Sciences, Frontier Science Center for Immunology and Metabolism, Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan UniversityCollege of Life Sciences, TaiKang Center for Life and Medical Sciences, Frontier Science Center for Immunology and Metabolism, Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan UniversityDepartment of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Hengyang Medical School, University of South ChinaCollege of Life Sciences, TaiKang Center for Life and Medical Sciences, Frontier Science Center for Immunology and Metabolism, Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan UniversityState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of MacauDepartment of Pediatric Intensive Care Unit, Anhui Provincial Children’s HospitalDepartment of Biochemistry, Rappaport Faculty of Medicine, Technion-Israel Institute of TechnologyCollege of Life Sciences, TaiKang Center for Life and Medical Sciences, Frontier Science Center for Immunology and Metabolism, Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan UniversityCollege of Life Sciences, TaiKang Center for Life and Medical Sciences, Frontier Science Center for Immunology and Metabolism, Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan UniversityCollege of Life Sciences, TaiKang Center for Life and Medical Sciences, Frontier Science Center for Immunology and Metabolism, Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan UniversityAbstract Endoplasmic reticulum (ER)-mitochondria contacts are critical for the regulation of lipid transport, synthesis, and metabolism. However, the molecular mechanism and physiological function of endoplasmic reticulum-mitochondrial contacts remain unclear. Here, we show that Mic19, a key subunit of MICOS (mitochondrial contact site and cristae organizing system) complex, regulates ER-mitochondria contacts by the EMC2-SLC25A46-Mic19 axis. Mic19 liver specific knockout (LKO) leads to the reduction of ER-mitochondrial contacts, mitochondrial lipid metabolism disorder, disorganization of mitochondrial cristae and mitochondrial unfolded protein stress response in mouse hepatocytes, impairing liver mitochondrial fatty acid β-oxidation and lipid metabolism, which may spontaneously trigger nonalcoholic steatohepatitis (NASH) and liver fibrosis in mice. Whereas, the re-expression of Mic19 in Mic19 LKO hepatocytes blocks the development of liver disease in mice. In addition, Mic19 overexpression suppresses MCD-induced fatty liver disease. Thus, our findings uncover the EMC2-SLC25A46-Mic19 axis as a pathway regulating ER-mitochondria contacts, and reveal that impairment of ER-mitochondria contacts may be a mechanism associated with the development of NASH and liver fibrosis.https://doi.org/10.1038/s41467-023-44057-6 |
| spellingShingle | Jun Dong Li Chen Fei Ye Junhui Tang Bing Liu Jiacheng Lin Pang-Hu Zhou Bin Lu Min Wu Jia-Hong Lu Jing-Jing He Simone Engelender Qingtao Meng Zhiyin Song He He Mic19 depletion impairs endoplasmic reticulum-mitochondrial contacts and mitochondrial lipid metabolism and triggers liver disease Nature Communications |
| title | Mic19 depletion impairs endoplasmic reticulum-mitochondrial contacts and mitochondrial lipid metabolism and triggers liver disease |
| title_full | Mic19 depletion impairs endoplasmic reticulum-mitochondrial contacts and mitochondrial lipid metabolism and triggers liver disease |
| title_fullStr | Mic19 depletion impairs endoplasmic reticulum-mitochondrial contacts and mitochondrial lipid metabolism and triggers liver disease |
| title_full_unstemmed | Mic19 depletion impairs endoplasmic reticulum-mitochondrial contacts and mitochondrial lipid metabolism and triggers liver disease |
| title_short | Mic19 depletion impairs endoplasmic reticulum-mitochondrial contacts and mitochondrial lipid metabolism and triggers liver disease |
| title_sort | mic19 depletion impairs endoplasmic reticulum mitochondrial contacts and mitochondrial lipid metabolism and triggers liver disease |
| url | https://doi.org/10.1038/s41467-023-44057-6 |
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