Membrane lipid composition modulates the organization of VDAC1, a mitochondrial gatekeeper
Abstract VDACs, the most abundant proteins in the outer mitochondrial membrane (MOM), are crucial for mitochondrial physiology. VDAC regulate metabolite and ion exchange, modulate calcium homeostasis, and play roles in numerous cellular events such as apoptosis, mitochondrial DNA (mtDNA) release, an...
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Nature Portfolio
2025-06-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-08311-5 |
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| author | Elodie Lafargue Jean-Pierre Duneau Nicolas Buzhinsky Pamela Ornelas Alexandre Ortega Varun Ravishankar James Sturgis Ignacio Casuso Lucie Bergdoll |
| author_facet | Elodie Lafargue Jean-Pierre Duneau Nicolas Buzhinsky Pamela Ornelas Alexandre Ortega Varun Ravishankar James Sturgis Ignacio Casuso Lucie Bergdoll |
| author_sort | Elodie Lafargue |
| collection | DOAJ |
| description | Abstract VDACs, the most abundant proteins in the outer mitochondrial membrane (MOM), are crucial for mitochondrial physiology. VDAC regulate metabolite and ion exchange, modulate calcium homeostasis, and play roles in numerous cellular events such as apoptosis, mitochondrial DNA (mtDNA) release, and different diseases. Mitochondrial function is closely tied to VDAC oligomerization, influencing key processes like mtDNA release and apoptosis, but the molecular drivers of this oligomerization remain unclear. In this study, we investigate the effects of three major MOM lipids on VDAC assemblies using atomic force microscopy and molecular dynamics simulations. Our results show that phosphatidylethanolamine and cholesterol regulate VDAC assembly, with the formation of stable lipid–protein organization of various size and compaction. Deviations from physiological lipid content disrupted native-like VDAC assemblies, highlighting the importance of lipid environment in VDAC organization. These findings underscore how lipid heterogeneity and changes in membranes influence VDAC function. |
| format | Article |
| id | doaj-art-4ec460e5e71a4da2a83fb95f399e0121 |
| institution | OA Journals |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-4ec460e5e71a4da2a83fb95f399e01212025-08-20T02:37:35ZengNature PortfolioCommunications Biology2399-36422025-06-018111210.1038/s42003-025-08311-5Membrane lipid composition modulates the organization of VDAC1, a mitochondrial gatekeeperElodie Lafargue0Jean-Pierre Duneau1Nicolas Buzhinsky2Pamela Ornelas3Alexandre Ortega4Varun Ravishankar5James Sturgis6Ignacio Casuso7Lucie Bergdoll8Turing Centre for Living System, Aix-Marseille Université, U1325 INSERM, DyNaMoLaboratoire d’Ingénierie des Systèmes Macromoléculaires, CNRS - Aix Marseille UniversitéTuring Centre for Living System, Aix-Marseille Université, U1325 INSERM, DyNaMoDepartment of Structural Biology, Max Planck Institute of BiophysicsTuring Centre for Living System, Aix-Marseille Université, U1325 INSERM, DyNaMoLaboratoire d’Ingénierie des Systèmes Macromoléculaires, CNRS - Aix Marseille UniversitéLaboratoire d’Ingénierie des Systèmes Macromoléculaires, CNRS - Aix Marseille UniversitéTuring Centre for Living System, Aix-Marseille Université, U1325 INSERM, DyNaMoLaboratoire d’Ingénierie des Systèmes Macromoléculaires, CNRS - Aix Marseille UniversitéAbstract VDACs, the most abundant proteins in the outer mitochondrial membrane (MOM), are crucial for mitochondrial physiology. VDAC regulate metabolite and ion exchange, modulate calcium homeostasis, and play roles in numerous cellular events such as apoptosis, mitochondrial DNA (mtDNA) release, and different diseases. Mitochondrial function is closely tied to VDAC oligomerization, influencing key processes like mtDNA release and apoptosis, but the molecular drivers of this oligomerization remain unclear. In this study, we investigate the effects of three major MOM lipids on VDAC assemblies using atomic force microscopy and molecular dynamics simulations. Our results show that phosphatidylethanolamine and cholesterol regulate VDAC assembly, with the formation of stable lipid–protein organization of various size and compaction. Deviations from physiological lipid content disrupted native-like VDAC assemblies, highlighting the importance of lipid environment in VDAC organization. These findings underscore how lipid heterogeneity and changes in membranes influence VDAC function.https://doi.org/10.1038/s42003-025-08311-5 |
| spellingShingle | Elodie Lafargue Jean-Pierre Duneau Nicolas Buzhinsky Pamela Ornelas Alexandre Ortega Varun Ravishankar James Sturgis Ignacio Casuso Lucie Bergdoll Membrane lipid composition modulates the organization of VDAC1, a mitochondrial gatekeeper Communications Biology |
| title | Membrane lipid composition modulates the organization of VDAC1, a mitochondrial gatekeeper |
| title_full | Membrane lipid composition modulates the organization of VDAC1, a mitochondrial gatekeeper |
| title_fullStr | Membrane lipid composition modulates the organization of VDAC1, a mitochondrial gatekeeper |
| title_full_unstemmed | Membrane lipid composition modulates the organization of VDAC1, a mitochondrial gatekeeper |
| title_short | Membrane lipid composition modulates the organization of VDAC1, a mitochondrial gatekeeper |
| title_sort | membrane lipid composition modulates the organization of vdac1 a mitochondrial gatekeeper |
| url | https://doi.org/10.1038/s42003-025-08311-5 |
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