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. 2021 Mar 16;34(11):108873.
doi: 10.1016/j.celrep.2021.108873.

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

Irene Anastasia  1 , Nicolò Ilacqua  1 , Andrea Raimondi  2 , Philippe Lemieux  3 , Rana Ghandehari-Alavijeh  3 , Guilhem Faure  4 , Sergei L Mekhedov  5 , Kevin J Williams  6 , Federico Caicci  7 , Giorgio Valle  7 , Marta Giacomello  7 , Ariel D Quiroga  8 , Richard Lehner  9 , Michael J Miksis  10 , Katalin Toth  11 , Thomas Q de Aguiar Vallim  12 , Eugene V Koonin  5 , Luca Scorrano  7 , Luca Pellegrini  13
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Free article

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

Irene Anastasia et al. Cell Rep. .
Free article

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.

Keywords: MAM; MUP; Rrbp1; VLDL; endoplasmic reticulum; inter-organelle contact; lipoprotein; liver metabolism; mitochondria; wrappER.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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