Dataset Information

PLIN5 interacts with FATP4 at membrane contact sites to promote lipid droplet-to-mitochondria fatty acid transport.

ABSTRACT: Cells adjust their metabolism by remodeling membrane contact sites that channel metabolites to different fates. Lipid droplet (LD)-mitochondria contacts change in response to fasting, cold exposure, and exercise. However, their function and mechanism of formation have remained controversial. We focused on perilipin 5 (PLIN5), an LD protein that tethers mitochondria, to probe the function and regulation of LD-mitochondria contacts. We demonstrate that efficient LD-to-mitochondria fatty acid (FA) trafficking and ß-oxidation during starvation of myoblasts are promoted by phosphorylation of PLIN5 and require an intact PLIN5 mitochondrial tethering domain. Using human and murine cells, we further identified the acyl-CoA synthetase, FATP4 (ACSVL4), as a mitochondrial interactor of PLIN5. The C-terminal domains of PLIN5 and FATP4 constitute a minimal protein interaction capable of inducing organelle contacts. Our work suggests that starvation leads to phosphorylation of PLIN5, lipolysis, and subsequent channeling of FAs from LDs to FATP4 on mitochondria for conversion to fatty-acyl-CoAs and subsequent oxidation.

SUBMITTER: Miner GE

PROVIDER: S-EPMC10525032 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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PLIN5 interacts with FATP4 at membrane contact sites to promote lipid droplet-to-mitochondria fatty acid transport.

Miner Gregory E GE So Christina M CM Edwards Whitney W Ragusa Joey V JV Wine Jonathan T JT Wong Gutierrez Daniel D Airola Michael V MV Herring Laura E LE Coleman Rosalind A RA Klett Eric L EL Cohen Sarah S

Developmental cell 20230607 14

Cells adjust their metabolism by remodeling membrane contact sites that channel metabolites to different fates. Lipid droplet (LD)-mitochondria contacts change in response to fasting, cold exposure, and exercise. However, their function and mechanism of formation have remained controversial. We focused on perilipin 5 (PLIN5), an LD protein that tethers mitochondria, to probe the function and regulation of LD-mitochondria contacts. We demonstrate that efficient LD-to-mitochondria fatty acid (FA) ...[more]

PMID: 37290445

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Project description:Background: Lipid droplets (LDs) establish a considerable number of contact sites with mitochondria to enable energy transfer and communication. In this study, we developed a fluorescent biosensor to image LD-mitochondria interactions at the nanoscale and further explored the function of LD-mediated matrix transmission in processes involving multi-organelle interactions. Methods: A fluorescent probe called C-Py (C21H19N3O2, 7-(diethylamino) coumarin-3-vinyl-4-pyridine acetonitrile) was designed and synthesized. Colocalization of C-Py and the commercial LD stain Nile Red was analyzed in HeLa cells. The fluorescence stability and signal to background ratio of C-Py under structured illumination microscopy (SIM) were compared to those of the commercial probe BODIPY493/503. The cytotoxicity of C-Py was assessed using CCK-8 assays. The uptake pattern of C-Py in HeLa cells was then observed under various temperatures, metabolic levels, and endocytosis levels. Contact sites between LDs and various organelles, such as mitochondria, nuclei, and cell membrane, were imaged and quantitated using SIM. Physical changes to the contact sites between LDs and mitochondria were monitored after lipopolysaccharide induction. Results: A LD-targeted fluorescent biosensor, C-Py, with good specificity, low background signal, excellent photostability, low cytotoxicity, and high cellular permeability was developed for tracking LD contact sites with multiple organelles using SIM. Using C-Py, the subcellular distribution and dynamic processes of LDs in living cells were observed under SIM. The formation of contact sites between LDs and multiple organelles was visualized at a resolution below ~200 nm. The number of LD-mitochondria contact sites formed was decreased by lipopolysaccharide treatment inducing an inflammatory environment. Conclusions: C-Py provides strategies for the design of ultra-highly selective biosensors and a new tool for investigating the role and regulation of LDs in living cells at the nanoscale.

Dataset Information

PLIN5 interacts with FATP4 at membrane contact sites to promote lipid droplet-to-mitochondria fatty acid transport.

Publications

PLIN5 interacts with FATP4 at membrane contact sites to promote lipid droplet-to-mitochondria fatty acid transport.

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