A three-organelle complex made by wrappER contacts with peroxisomes and mitochondria responds to liver lipid flux changes.

TitleA three-organelle complex made by wrappER contacts with peroxisomes and mitochondria responds to liver lipid flux changes.
Publication TypeJournal Article
Year of Publication2022
AuthorsIlacqua, N, Anastasia, I, Raimondi, A, Lemieux, P, Vallim, TQ de Aguia, Toth, K, Koonin, EV, Pellegrini, L
JournalJ Cell Sci
Volume135
Issue5
Date Published2022 03 01
ISSN1477-9137
KeywordsAnimals, Lipid Metabolism, Liver, Mice, Mitochondria, Peroxisomes, Proteomics
Abstract

Hepatic lipid homeostasis depends on intracellular pathways that respire fatty acid in peroxisomes and mitochondria, and on systemic pathways that secrete fatty acid into the bloodstream, either free or condensed in very-low-density lipoprotein (VLDL) triglycerides. These systemic and intracellular pathways are interdependent, but it is unclear whether and how they integrate into a single cellular circuit. Here, we report that mouse liver wrappER, a distinct endoplasmic reticulum (ER) compartment with apparent fatty acid- and VLDL-secretion functions, connects peroxisomes and mitochondria. Correlative light electron microscopy, quantitative serial section electron tomography and three-dimensional organelle reconstruction analysis show that the number of peroxisome-wrappER-mitochondria complexes changes throughout fasting-to-feeding transitions and doubles when VLDL synthesis stops following acute genetic ablation of Mttp in the liver. Quantitative proteomic analysis of peroxisome-wrappER-mitochondria complex-enriched fractions indicates that the loss of Mttp upregulates global fatty acid β-oxidation, thereby integrating the dynamics of this three-organelle association into hepatic fatty acid flux responses. Therefore, liver lipid homeostasis occurs through the convergence of systemic and intracellular fatty acid-elimination pathways in the peroxisome-wrappER-mitochondria complex.

DOI10.1242/jcs.259091
Alternate JournalJ Cell Sci
PubMed ID34672330
PubMed Central IDPMC8627550
Grant ListMOP-81142 / / CIHR / Canada
R01 HL122677 / HL / NHLBI NIH HHS / United States
HL122677 / NH / NIH HHS / United States
201603PJT-365052 / / CIHR / Canada
R01 DK112119 / DK / NIDDK NIH HHS / United States