Proximity proteomics reveals a mechanism of fatty acid transfer at lipid droplet-mitochondria- endoplasmic reticulum contact sites
Abstract Membrane contact sites between organelles are critical for the transfer of biomolecules. Lipid droplets store fatty acids and form contacts with mitochondria, which regulate fatty acid oxidation and adenosine triphosphate production. Protein compartmentalization at lipid droplet-mitochondri...
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Nature Portfolio
2025-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-57405-5 |
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| author | Ayenachew Bezawork-Geleta Camille J. Devereux Stacey N. Keenan Jieqiong Lou Ellie Cho Shuai Nie David P. De Souza Vinod K. Narayana Nicole A. Siddall Carlos H. M. Rodrigues Stephanie Portelli Tenghao Zheng Hieu T. Nim Mirana Ramialison Gary R. Hime Garron T. Dodd Elizabeth Hinde David B. Ascher David A. Stroud Matthew J. Watt |
| author_facet | Ayenachew Bezawork-Geleta Camille J. Devereux Stacey N. Keenan Jieqiong Lou Ellie Cho Shuai Nie David P. De Souza Vinod K. Narayana Nicole A. Siddall Carlos H. M. Rodrigues Stephanie Portelli Tenghao Zheng Hieu T. Nim Mirana Ramialison Gary R. Hime Garron T. Dodd Elizabeth Hinde David B. Ascher David A. Stroud Matthew J. Watt |
| author_sort | Ayenachew Bezawork-Geleta |
| collection | DOAJ |
| description | Abstract Membrane contact sites between organelles are critical for the transfer of biomolecules. Lipid droplets store fatty acids and form contacts with mitochondria, which regulate fatty acid oxidation and adenosine triphosphate production. Protein compartmentalization at lipid droplet-mitochondria contact sites and their effects on biological processes are poorly described. Using proximity-dependent biotinylation methods, we identify 71 proteins at lipid droplet-mitochondria contact sites, including a multimeric complex containing extended synaptotagmin (ESYT) 1, ESYT2, and VAMP Associated Protein B and C (VAPB). High resolution imaging confirms localization of this complex at the interface of lipid droplet-mitochondria-endoplasmic reticulum where it likely transfers fatty acids to enable β-oxidation. Deletion of ESYT1, ESYT2 or VAPB limits lipid droplet-derived fatty acid oxidation, resulting in depletion of tricarboxylic acid cycle metabolites, remodeling of the cellular lipidome, and induction of lipotoxic stress. These findings were recapitulated in Esyt1 and Esyt2 deficient mice. Our study uncovers a fundamental mechanism that is required for lipid droplet-derived fatty acid oxidation and cellular lipid homeostasis, with implications for metabolic diseases and survival. |
| format | Article |
| id | doaj-art-3eefcf64f56544bca1b0553f1420eff5 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-3eefcf64f56544bca1b0553f1420eff52025-08-20T03:06:00ZengNature PortfolioNature Communications2041-17232025-03-0116112310.1038/s41467-025-57405-5Proximity proteomics reveals a mechanism of fatty acid transfer at lipid droplet-mitochondria- endoplasmic reticulum contact sitesAyenachew Bezawork-Geleta0Camille J. Devereux1Stacey N. Keenan2Jieqiong Lou3Ellie Cho4Shuai Nie5David P. De Souza6Vinod K. Narayana7Nicole A. Siddall8Carlos H. M. Rodrigues9Stephanie Portelli10Tenghao Zheng11Hieu T. Nim12Mirana Ramialison13Gary R. Hime14Garron T. Dodd15Elizabeth Hinde16David B. Ascher17David A. Stroud18Matthew J. Watt19Department of Anatomy and Physiology, The University of MelbourneDepartment of Anatomy and Physiology, The University of MelbourneDepartment of Anatomy and Physiology, The University of MelbourneSchool of Physics, The University of MelbourneBiological Optical Microscopy Platform (BOMP), The University of MelbourneMelbourne Mass Spectrometry and Proteomics Facility (MMSPF), Bio21 Molecular Science and Biotechnology Institute, University of MelbourneMetabolomics Australia, Bio21 Molecular Science and Biotechnology Institute, University of MelbourneMetabolomics Australia, Bio21 Molecular Science and Biotechnology Institute, University of MelbourneDepartment of Anatomy and Physiology, The University of MelbourneSchool of Chemistry and Molecular Biosciences, University of QueenslandSchool of Chemistry and Molecular Biosciences, University of QueenslandSchool of Biological Sciences, Monash UniversityMurdoch Children’s Research Institute, reNEW Novo Nordisk Foundation for Stem Cell MedicineMurdoch Children’s Research Institute, reNEW Novo Nordisk Foundation for Stem Cell MedicineDepartment of Anatomy and Physiology, The University of MelbourneDepartment of Anatomy and Physiology, The University of MelbourneSchool of Physics, The University of MelbourneSchool of Chemistry and Molecular Biosciences, University of QueenslandMurdoch Children’s Research Institute, reNEW Novo Nordisk Foundation for Stem Cell MedicineDepartment of Anatomy and Physiology, The University of MelbourneAbstract Membrane contact sites between organelles are critical for the transfer of biomolecules. Lipid droplets store fatty acids and form contacts with mitochondria, which regulate fatty acid oxidation and adenosine triphosphate production. Protein compartmentalization at lipid droplet-mitochondria contact sites and their effects on biological processes are poorly described. Using proximity-dependent biotinylation methods, we identify 71 proteins at lipid droplet-mitochondria contact sites, including a multimeric complex containing extended synaptotagmin (ESYT) 1, ESYT2, and VAMP Associated Protein B and C (VAPB). High resolution imaging confirms localization of this complex at the interface of lipid droplet-mitochondria-endoplasmic reticulum where it likely transfers fatty acids to enable β-oxidation. Deletion of ESYT1, ESYT2 or VAPB limits lipid droplet-derived fatty acid oxidation, resulting in depletion of tricarboxylic acid cycle metabolites, remodeling of the cellular lipidome, and induction of lipotoxic stress. These findings were recapitulated in Esyt1 and Esyt2 deficient mice. Our study uncovers a fundamental mechanism that is required for lipid droplet-derived fatty acid oxidation and cellular lipid homeostasis, with implications for metabolic diseases and survival.https://doi.org/10.1038/s41467-025-57405-5 |
| spellingShingle | Ayenachew Bezawork-Geleta Camille J. Devereux Stacey N. Keenan Jieqiong Lou Ellie Cho Shuai Nie David P. De Souza Vinod K. Narayana Nicole A. Siddall Carlos H. M. Rodrigues Stephanie Portelli Tenghao Zheng Hieu T. Nim Mirana Ramialison Gary R. Hime Garron T. Dodd Elizabeth Hinde David B. Ascher David A. Stroud Matthew J. Watt Proximity proteomics reveals a mechanism of fatty acid transfer at lipid droplet-mitochondria- endoplasmic reticulum contact sites Nature Communications |
| title | Proximity proteomics reveals a mechanism of fatty acid transfer at lipid droplet-mitochondria- endoplasmic reticulum contact sites |
| title_full | Proximity proteomics reveals a mechanism of fatty acid transfer at lipid droplet-mitochondria- endoplasmic reticulum contact sites |
| title_fullStr | Proximity proteomics reveals a mechanism of fatty acid transfer at lipid droplet-mitochondria- endoplasmic reticulum contact sites |
| title_full_unstemmed | Proximity proteomics reveals a mechanism of fatty acid transfer at lipid droplet-mitochondria- endoplasmic reticulum contact sites |
| title_short | Proximity proteomics reveals a mechanism of fatty acid transfer at lipid droplet-mitochondria- endoplasmic reticulum contact sites |
| title_sort | proximity proteomics reveals a mechanism of fatty acid transfer at lipid droplet mitochondria endoplasmic reticulum contact sites |
| url | https://doi.org/10.1038/s41467-025-57405-5 |
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