Proximity proteomics reveals a mechanism of fatty acid transfer at lipid droplet-mitochondria- endoplasmic reticulum contact sites

Ayenachew Bezawork-Geleta, Camille J. Devereux, Stacey N. Keenan, Jieqiong Lou, Ellie Cho, Shuai Nie, David P. 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 and Matthew J. Watt ()
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Ayenachew Bezawork-Geleta: The University of Melbourne
Camille J. Devereux: The University of Melbourne
Stacey N. Keenan: The University of Melbourne
Jieqiong Lou: The University of Melbourne
Ellie Cho: The University of Melbourne
Shuai Nie: University of Melbourne
David P. Souza: University of Melbourne
Vinod K. Narayana: University of Melbourne
Nicole A. Siddall: The University of Melbourne
Carlos H. M. Rodrigues: University of Queensland
Stephanie Portelli: University of Queensland
Tenghao Zheng: Monash University
Hieu T. Nim: reNEW Novo Nordisk Foundation for Stem Cell Medicine
Mirana Ramialison: reNEW Novo Nordisk Foundation for Stem Cell Medicine
Gary R. Hime: The University of Melbourne
Garron T. Dodd: The University of Melbourne
Elizabeth Hinde: The University of Melbourne
David B. Ascher: University of Queensland
David A. Stroud: reNEW Novo Nordisk Foundation for Stem Cell Medicine
Matthew J. Watt: The University of Melbourne

Nature Communications, 2025, vol. 16, issue 1, 1-23

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57405-5

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