Phospholipids are imported into mitochondria by VDAC, a dimeric beta barrel scramblase
Abstract Mitochondria are double-membrane-bounded organelles that depend critically on phospholipids supplied by the endoplasmic reticulum. These lipids must cross the outer membrane to support mitochondrial function, but how they do this is unclear. We identify the Voltage Dependent Anion Channel (...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-12-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-43570-y |
| _version_ | 1827581504329351168 |
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| author | Helene Jahn Ladislav Bartoš Grace I. Dearden Jeremy S. Dittman Joost C. M. Holthuis Robert Vácha Anant K. Menon |
| author_facet | Helene Jahn Ladislav Bartoš Grace I. Dearden Jeremy S. Dittman Joost C. M. Holthuis Robert Vácha Anant K. Menon |
| author_sort | Helene Jahn |
| collection | DOAJ |
| description | Abstract Mitochondria are double-membrane-bounded organelles that depend critically on phospholipids supplied by the endoplasmic reticulum. These lipids must cross the outer membrane to support mitochondrial function, but how they do this is unclear. We identify the Voltage Dependent Anion Channel (VDAC), an abundant outer membrane protein, as a scramblase-type lipid transporter that catalyzes lipid entry. On reconstitution into membrane vesicles, dimers of human VDAC1 and VDAC2 catalyze rapid transbilayer translocation of phospholipids by a mechanism that is unrelated to their channel activity. Coarse-grained molecular dynamics simulations of VDAC1 reveal that lipid scrambling occurs at a specific dimer interface where polar residues induce large water defects and bilayer thinning. The rate of phospholipid import into yeast mitochondria is an order of magnitude lower in the absence of VDAC homologs, indicating that VDACs provide the main pathway for lipid entry. Thus, VDAC isoforms, members of a superfamily of beta barrel proteins, moonlight as a class of phospholipid scramblases - distinct from alpha-helical scramblase proteins - that act to import lipids into mitochondria. |
| first_indexed | 2024-03-08T22:37:28Z |
| format | Article |
| id | doaj.art-80090a11e13246b496e3a818de0be8af |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-08T22:37:28Z |
| publishDate | 2023-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-80090a11e13246b496e3a818de0be8af2023-12-17T12:23:14ZengNature PortfolioNature Communications2041-17232023-12-0114111610.1038/s41467-023-43570-yPhospholipids are imported into mitochondria by VDAC, a dimeric beta barrel scramblaseHelene Jahn0Ladislav Bartoš1Grace I. Dearden2Jeremy S. Dittman3Joost C. M. Holthuis4Robert Vácha5Anant K. Menon6Department of Biochemistry, Weill Cornell Medical CollegeCEITEC - Central European Institute of Technology, Masaryk UniversityDepartment of Biochemistry, Weill Cornell Medical CollegeDepartment of Biochemistry, Weill Cornell Medical CollegeDepartment of Molecular Cell Biology, University of OsnabrückCEITEC - Central European Institute of Technology, Masaryk UniversityDepartment of Biochemistry, Weill Cornell Medical CollegeAbstract Mitochondria are double-membrane-bounded organelles that depend critically on phospholipids supplied by the endoplasmic reticulum. These lipids must cross the outer membrane to support mitochondrial function, but how they do this is unclear. We identify the Voltage Dependent Anion Channel (VDAC), an abundant outer membrane protein, as a scramblase-type lipid transporter that catalyzes lipid entry. On reconstitution into membrane vesicles, dimers of human VDAC1 and VDAC2 catalyze rapid transbilayer translocation of phospholipids by a mechanism that is unrelated to their channel activity. Coarse-grained molecular dynamics simulations of VDAC1 reveal that lipid scrambling occurs at a specific dimer interface where polar residues induce large water defects and bilayer thinning. The rate of phospholipid import into yeast mitochondria is an order of magnitude lower in the absence of VDAC homologs, indicating that VDACs provide the main pathway for lipid entry. Thus, VDAC isoforms, members of a superfamily of beta barrel proteins, moonlight as a class of phospholipid scramblases - distinct from alpha-helical scramblase proteins - that act to import lipids into mitochondria.https://doi.org/10.1038/s41467-023-43570-y |
| spellingShingle | Helene Jahn Ladislav Bartoš Grace I. Dearden Jeremy S. Dittman Joost C. M. Holthuis Robert Vácha Anant K. Menon Phospholipids are imported into mitochondria by VDAC, a dimeric beta barrel scramblase Nature Communications |
| title | Phospholipids are imported into mitochondria by VDAC, a dimeric beta barrel scramblase |
| title_full | Phospholipids are imported into mitochondria by VDAC, a dimeric beta barrel scramblase |
| title_fullStr | Phospholipids are imported into mitochondria by VDAC, a dimeric beta barrel scramblase |
| title_full_unstemmed | Phospholipids are imported into mitochondria by VDAC, a dimeric beta barrel scramblase |
| title_short | Phospholipids are imported into mitochondria by VDAC, a dimeric beta barrel scramblase |
| title_sort | phospholipids are imported into mitochondria by vdac a dimeric beta barrel scramblase |
| url | https://doi.org/10.1038/s41467-023-43570-y |
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