Mitochondria-rough-ER contacts in the liver regulate systemic lipid homeostasis

Irene Anastasia, Nicolò Ilacqua, Andrea Raimondi, Philippe Lemieux, Rana Ghandehari-Alavijeh, Guilhem Faure, Sergei L. Mekhedov, Kevin J. Williams, Federico Caicci, Giorgio Valle, Marta Giacomello, Ariel D. Quiroga, Richard Lehner, Michael J. Miksis, Katalin Toth, Thomas Q. de Aguiar Vallim, Eugene V. Koonin, Luca Scorrano, Luca Pellegrini*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

75 Scopus citations

Abstract

Contacts between organelles create microdomains that play major roles in regulating key intracellular activities and signaling pathways, but whether they also regulate systemic functions remains unknown. Here, we report the ultrastructural organization and dynamics of the inter-organellar contact established by sheets of curved rough endoplasmic reticulum closely wrapped around the mitochondria (wrappER). To elucidate the in vivo function of this contact, mouse liver fractions enriched in wrappER-associated mitochondria are analyzed by transcriptomics, proteomics, and lipidomics. The biochemical signature of the wrappER points to a role in the biogenesis of very-low-density lipoproteins (VLDL). Altering wrappER-mitochondria contacts curtails VLDL secretion and increases hepatic fatty acids, lipid droplets, and neutral lipid content. Conversely, acute liver-specific ablation of Mttp, the most upstream regulator of VLDL biogenesis, recapitulates this hepatic dyslipidemia phenotype and promotes remodeling of the wrappER-mitochondria contact. The discovery that liver wrappER-mitochondria contacts participate in VLDL biology suggests an involvement of inter-organelle contacts in systemic lipid homeostasis.

Original languageEnglish (US)
Article number108873
JournalCell reports
Volume34
Issue number11
DOIs
StatePublished - Mar 16 2021

Keywords

  • MAM
  • MUP
  • Rrbp1
  • VLDL
  • endoplasmic reticulum
  • inter-organelle contact
  • lipoprotein
  • liver metabolism
  • mitochondria
  • wrappER

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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