MMD collaborates with ACSL4 and MBOAT7 to promote polyunsaturated phosphatidylinositol remodeling and susceptibility to ferroptosis
Summary: Ferroptosis is a form of regulated cell death with roles in degenerative diseases and cancer. Excessive iron-catalyzed peroxidation of membrane phospholipids, especially those containing the polyunsaturated fatty acid arachidonic acid (AA), is central in driving ferroptosis. Here, we reveal...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-09-01
|
| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723010343 |
| _version_ | 1797689532578004992 |
|---|---|
| author | Vaishnavi V. Phadnis Jamie Snider Venkateshwari Varadharajan Iyappan Ramachandiran Amy A. Deik Zon Weng Lai Tenzin Kunchok Elinor Ng Eaton Carolin Sebastiany Anna Lyakisheva Kyle D. Vaccaro Juliet Allen Zhong Yao Victoria Wong Betty Geng Kipp Weiskopf Clary B. Clish J. Mark Brown Igor Stagljar Robert A. Weinberg Whitney S. Henry |
| author_facet | Vaishnavi V. Phadnis Jamie Snider Venkateshwari Varadharajan Iyappan Ramachandiran Amy A. Deik Zon Weng Lai Tenzin Kunchok Elinor Ng Eaton Carolin Sebastiany Anna Lyakisheva Kyle D. Vaccaro Juliet Allen Zhong Yao Victoria Wong Betty Geng Kipp Weiskopf Clary B. Clish J. Mark Brown Igor Stagljar Robert A. Weinberg Whitney S. Henry |
| author_sort | Vaishnavi V. Phadnis |
| collection | DOAJ |
| description | Summary: Ferroptosis is a form of regulated cell death with roles in degenerative diseases and cancer. Excessive iron-catalyzed peroxidation of membrane phospholipids, especially those containing the polyunsaturated fatty acid arachidonic acid (AA), is central in driving ferroptosis. Here, we reveal that an understudied Golgi-resident scaffold protein, MMD, promotes susceptibility to ferroptosis in ovarian and renal carcinoma cells in an ACSL4- and MBOAT7-dependent manner. Mechanistically, MMD physically interacts with both ACSL4 and MBOAT7, two enzymes that catalyze sequential steps to incorporate AA in phosphatidylinositol (PI) lipids. Thus, MMD increases the flux of AA into PI, resulting in heightened cellular levels of AA-PI and other AA-containing phospholipid species. This molecular mechanism points to a pro-ferroptotic role for MBOAT7 and AA-PI, with potential therapeutic implications, and reveals that MMD is an important regulator of cellular lipid metabolism. |
| first_indexed | 2024-03-12T01:46:55Z |
| format | Article |
| id | doaj.art-f1a03612f457448787c70b44eca61b6d |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-12T01:46:55Z |
| publishDate | 2023-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-f1a03612f457448787c70b44eca61b6d2023-09-09T04:55:00ZengElsevierCell Reports2211-12472023-09-01429113023MMD collaborates with ACSL4 and MBOAT7 to promote polyunsaturated phosphatidylinositol remodeling and susceptibility to ferroptosisVaishnavi V. Phadnis0Jamie Snider1Venkateshwari Varadharajan2Iyappan Ramachandiran3Amy A. Deik4Zon Weng Lai5Tenzin Kunchok6Elinor Ng Eaton7Carolin Sebastiany8Anna Lyakisheva9Kyle D. Vaccaro10Juliet Allen11Zhong Yao12Victoria Wong13Betty Geng14Kipp Weiskopf15Clary B. Clish16J. Mark Brown17Igor Stagljar18Robert A. Weinberg19Whitney S. Henry20Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, MIT, Cambridge, MA 02139, USA; Harvard Medical School, Boston, MA 02115, USADonnelly Centre, University of Toronto, Toronto, ON M5S 3E1, CanadaDepartment of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USADepartment of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USABroad Institute of MIT and Harvard, Cambridge, MA 02142, USADepartment of Molecular Metabolism, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USAWhitehead Institute for Biomedical Research, Cambridge, MA 02142, USAWhitehead Institute for Biomedical Research, Cambridge, MA 02142, USAWhitehead Institute for Biomedical Research, Cambridge, MA 02142, USADonnelly Centre, University of Toronto, Toronto, ON M5S 3E1, CanadaWhitehead Institute for Biomedical Research, Cambridge, MA 02142, USAWhitehead Institute for Biomedical Research, Cambridge, MA 02142, USADonnelly Centre, University of Toronto, Toronto, ON M5S 3E1, CanadaDonnelly Centre, University of Toronto, Toronto, ON M5S 3E1, CanadaDonnelly Centre, University of Toronto, Toronto, ON M5S 3E1, CanadaWhitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Dana-Farber Cancer Institute, Boston, MA 02215, USABroad Institute of MIT and Harvard, Cambridge, MA 02142, USADepartment of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USADonnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Biochemistry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; Mediterranean Institute for Life Sciences, 21000 Split, CroatiaWhitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, MIT, Cambridge, MA 02139, USA; Corresponding authorWhitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Corresponding authorSummary: Ferroptosis is a form of regulated cell death with roles in degenerative diseases and cancer. Excessive iron-catalyzed peroxidation of membrane phospholipids, especially those containing the polyunsaturated fatty acid arachidonic acid (AA), is central in driving ferroptosis. Here, we reveal that an understudied Golgi-resident scaffold protein, MMD, promotes susceptibility to ferroptosis in ovarian and renal carcinoma cells in an ACSL4- and MBOAT7-dependent manner. Mechanistically, MMD physically interacts with both ACSL4 and MBOAT7, two enzymes that catalyze sequential steps to incorporate AA in phosphatidylinositol (PI) lipids. Thus, MMD increases the flux of AA into PI, resulting in heightened cellular levels of AA-PI and other AA-containing phospholipid species. This molecular mechanism points to a pro-ferroptotic role for MBOAT7 and AA-PI, with potential therapeutic implications, and reveals that MMD is an important regulator of cellular lipid metabolism.http://www.sciencedirect.com/science/article/pii/S2211124723010343CP: Cell biology |
| spellingShingle | Vaishnavi V. Phadnis Jamie Snider Venkateshwari Varadharajan Iyappan Ramachandiran Amy A. Deik Zon Weng Lai Tenzin Kunchok Elinor Ng Eaton Carolin Sebastiany Anna Lyakisheva Kyle D. Vaccaro Juliet Allen Zhong Yao Victoria Wong Betty Geng Kipp Weiskopf Clary B. Clish J. Mark Brown Igor Stagljar Robert A. Weinberg Whitney S. Henry MMD collaborates with ACSL4 and MBOAT7 to promote polyunsaturated phosphatidylinositol remodeling and susceptibility to ferroptosis Cell Reports CP: Cell biology |
| title | MMD collaborates with ACSL4 and MBOAT7 to promote polyunsaturated phosphatidylinositol remodeling and susceptibility to ferroptosis |
| title_full | MMD collaborates with ACSL4 and MBOAT7 to promote polyunsaturated phosphatidylinositol remodeling and susceptibility to ferroptosis |
| title_fullStr | MMD collaborates with ACSL4 and MBOAT7 to promote polyunsaturated phosphatidylinositol remodeling and susceptibility to ferroptosis |
| title_full_unstemmed | MMD collaborates with ACSL4 and MBOAT7 to promote polyunsaturated phosphatidylinositol remodeling and susceptibility to ferroptosis |
| title_short | MMD collaborates with ACSL4 and MBOAT7 to promote polyunsaturated phosphatidylinositol remodeling and susceptibility to ferroptosis |
| title_sort | mmd collaborates with acsl4 and mboat7 to promote polyunsaturated phosphatidylinositol remodeling and susceptibility to ferroptosis |
| topic | CP: Cell biology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723010343 |
| work_keys_str_mv | AT vaishnavivphadnis mmdcollaborateswithacsl4andmboat7topromotepolyunsaturatedphosphatidylinositolremodelingandsusceptibilitytoferroptosis AT jamiesnider mmdcollaborateswithacsl4andmboat7topromotepolyunsaturatedphosphatidylinositolremodelingandsusceptibilitytoferroptosis AT venkateshwarivaradharajan mmdcollaborateswithacsl4andmboat7topromotepolyunsaturatedphosphatidylinositolremodelingandsusceptibilitytoferroptosis AT iyappanramachandiran mmdcollaborateswithacsl4andmboat7topromotepolyunsaturatedphosphatidylinositolremodelingandsusceptibilitytoferroptosis AT amyadeik mmdcollaborateswithacsl4andmboat7topromotepolyunsaturatedphosphatidylinositolremodelingandsusceptibilitytoferroptosis AT zonwenglai mmdcollaborateswithacsl4andmboat7topromotepolyunsaturatedphosphatidylinositolremodelingandsusceptibilitytoferroptosis AT tenzinkunchok mmdcollaborateswithacsl4andmboat7topromotepolyunsaturatedphosphatidylinositolremodelingandsusceptibilitytoferroptosis AT elinorngeaton mmdcollaborateswithacsl4andmboat7topromotepolyunsaturatedphosphatidylinositolremodelingandsusceptibilitytoferroptosis AT carolinsebastiany mmdcollaborateswithacsl4andmboat7topromotepolyunsaturatedphosphatidylinositolremodelingandsusceptibilitytoferroptosis AT annalyakisheva mmdcollaborateswithacsl4andmboat7topromotepolyunsaturatedphosphatidylinositolremodelingandsusceptibilitytoferroptosis AT kyledvaccaro mmdcollaborateswithacsl4andmboat7topromotepolyunsaturatedphosphatidylinositolremodelingandsusceptibilitytoferroptosis AT julietallen mmdcollaborateswithacsl4andmboat7topromotepolyunsaturatedphosphatidylinositolremodelingandsusceptibilitytoferroptosis AT zhongyao mmdcollaborateswithacsl4andmboat7topromotepolyunsaturatedphosphatidylinositolremodelingandsusceptibilitytoferroptosis AT victoriawong mmdcollaborateswithacsl4andmboat7topromotepolyunsaturatedphosphatidylinositolremodelingandsusceptibilitytoferroptosis AT bettygeng mmdcollaborateswithacsl4andmboat7topromotepolyunsaturatedphosphatidylinositolremodelingandsusceptibilitytoferroptosis AT kippweiskopf mmdcollaborateswithacsl4andmboat7topromotepolyunsaturatedphosphatidylinositolremodelingandsusceptibilitytoferroptosis AT clarybclish mmdcollaborateswithacsl4andmboat7topromotepolyunsaturatedphosphatidylinositolremodelingandsusceptibilitytoferroptosis AT jmarkbrown mmdcollaborateswithacsl4andmboat7topromotepolyunsaturatedphosphatidylinositolremodelingandsusceptibilitytoferroptosis AT igorstagljar mmdcollaborateswithacsl4andmboat7topromotepolyunsaturatedphosphatidylinositolremodelingandsusceptibilitytoferroptosis AT robertaweinberg mmdcollaborateswithacsl4andmboat7topromotepolyunsaturatedphosphatidylinositolremodelingandsusceptibilitytoferroptosis AT whitneyshenry mmdcollaborateswithacsl4andmboat7topromotepolyunsaturatedphosphatidylinositolremodelingandsusceptibilitytoferroptosis |