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Functional multi-organelle units control inflammatory lipid metabolism of macrophages

Affiliations
  • 1Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
  • 2Center of Chronic Immunodeficiency, Medical Center University of Freiburg, Freiburg, Germany.
  • 3International Max Planck Research School for Immunobiology, Epigenetics and Metabolism, Freiburg, Germany.
  • 4Faculty of Biology, University of Freiburg, Freiburg, Germany.
  • 5Bioinformatics Core Facility, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
  • 6Institute-Associated Research Group: Cell Adhesion and Cell Polarity, Institute of Medical Biochemistry, ZMBE, University of Munster, Munster, Germany.
  • 7Institute of Immunology, University of Munster, Munster, Germany.
  • 8Metabolomics Core Facility, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
  • 9Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany. rambold@ie-freiburg.mpg.de.
  • 10Center of Chronic Immunodeficiency, Medical Center University of Freiburg, Freiburg, Germany. rambold@ie-freiburg.mpg.de.

Published on:

July 5, 2024

Abstract

Eukaryotic cells contain several membrane-separated organelles to compartmentalize distinct metabolic reactions. However, it has remained unclear how these organelle systems are coordinated when cells adapt metabolic pathways to support their development, survival or effector functions. Here we present OrgaPlexing, a multi-spectral organelle imaging approach for the comprehensive mapping of six key metabolic organelles and their interactions. We use this analysis on macrophages, immune cells that undergo rapid metabolic switches upon sensing bacterial and inflammatory stimuli. Our results identify lipid droplets (LDs) as primary inflammatory responder organelle, which forms three- and four-way interactions with other organelles. While clusters with endoplasmic reticulum (ER) and mitochondria (mitochondria-ER-LD unit) help supply fatty acids for LD growth, the additional recruitment of peroxisomes (mitochondria-ER-peroxisome-LD unit) supports fatty acid efflux from LDs. Interference with individual components of these units has direct functional consequences for inflammatory lipid mediator synthesis. Together, we show that macrophages form functional multi-organellar units to support metabolic adaptation and provide an experimental strategy to identify organelle-metabolic signalling hubs.

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