ORP5 and ORP8 orchestrate lipid droplet biogenesis and maintenance at ER-mitochondria contact sites

Lipid droplets (LDs) are the primary organelles of lipid storage, buffering energy fluctuations of the cell. They store neutral lipids in their core that is surrounded by a protein-decorated phospholipid monolayer. LDs arise from the endoplasmic reticulum (ER). The ER protein seipin, localizing at E...

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Published in:	The Journal of cell biology Vol. 221; no. 9; p. 1
Main Authors:	Guyard, Valentin, Monteiro-Cardoso, Vera Filipa, Omrane, Mohyeddine, Sauvanet, Cécile, Houcine, Audrey, Boulogne, Claire, Ben Mbarek, Kalthoum, Vitale, Nicolas, Faklaris, Orestis, El Khallouki, Naima, Thiam, Abdou Rachid, Giordano, Francesca
Format:	Journal Article
Language:	English
Published:	United States Rockefeller University Press 05-09-2022
Subjects:	Biochemistry Biosynthesis Crosstalk Droplets Endoplasmic reticulum Endoplasmic Reticulum - metabolism Energy storage Life Sciences Lipid Droplets - metabolism Lipid Metabolism Lipid transfer proteins Lipids Membranes Mitochondria Mitochondria - metabolism Nucleation Organelles Phosphatidic acid Phospholipids Phospholipids - metabolism Proteins Receptors, Steroid - metabolism Biochemistry, Organelles
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Summary:	Lipid droplets (LDs) are the primary organelles of lipid storage, buffering energy fluctuations of the cell. They store neutral lipids in their core that is surrounded by a protein-decorated phospholipid monolayer. LDs arise from the endoplasmic reticulum (ER). The ER protein seipin, localizing at ER-LD junctions, controls LD nucleation and growth. However, how LD biogenesis is spatially and temporally coordinated remains elusive. Here, we show that the lipid transfer proteins ORP5 and ORP8 control LD biogenesis at mitochondria-associated ER membrane (MAM) subdomains, enriched in phosphatidic acid. We found that ORP5/8 regulates seipin recruitment to these MAM-LD contacts, and their loss impairs LD biogenesis. Importantly, the integrity of ER-mitochondria contact sites is crucial for ORP5/8 function in regulating seipin-mediated LD biogenesis. Our study uncovers an unprecedented ORP5/8 role in orchestrating LD biogenesis and maturation at MAMs and brings novel insights into the metabolic crosstalk between mitochondria, ER, and LDs at the membrane contact sites.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 V. Guyard, V.F. Monteiro-Cardoso, and M. Omrane contributed equally to this paper. A.R. Thiam and F. Giordano share equal senior authorship.
ISSN:	0021-9525 1540-8140 1540-8140
DOI:	10.1083/jcb.202112107