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Autophagy regulates fatty acid availability for oxidative phosphorylation through mitochondria-endoplasmic reticulum contact sites

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  • Claudie Bosc

    (Cancer Research Center of Toulouse (CRCT), INSERM U1037, CNRS ERL5294, University of Toulouse
    Equipe labellisée, La Ligue contre le Cancer)

  • Nicolas Broin

    (Cancer Research Center of Toulouse (CRCT), INSERM U1037, CNRS ERL5294, University of Toulouse
    Equipe labellisée, La Ligue contre le Cancer)

  • Marjorie Fanjul

    (Cancer Research Center of Toulouse (CRCT), INSERM U1037, CNRS ERL5294, University of Toulouse
    Equipe labellisée, La Ligue contre le Cancer)

  • Estelle Saland

    (Cancer Research Center of Toulouse (CRCT), INSERM U1037, CNRS ERL5294, University of Toulouse
    Equipe labellisée, La Ligue contre le Cancer)

  • Thomas Farge

    (Cancer Research Center of Toulouse (CRCT), INSERM U1037, CNRS ERL5294, University of Toulouse
    Equipe labellisée, La Ligue contre le Cancer)

  • Charly Courdy

    (Cancer Research Center of Toulouse (CRCT), INSERM U1037, CNRS ERL5294, University of Toulouse
    Equipe labellisée, La Ligue contre le Cancer)

  • Aurélie Batut

    (MetaToul-MetaboHUB, National Infrastructure of Metabolomics and Fluxomics)

  • Rawand Masoud

    (Aix Marseille Université, CNRS, INSERM, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille)

  • Clément Larrue

    (Translational Research Centre in Onco-hematology, Faculty of Medicine, University of Geneva)

  • Sarah Skuli

    (Cancer Research Center of Toulouse (CRCT), INSERM U1037, CNRS ERL5294, University of Toulouse
    Equipe labellisée, La Ligue contre le Cancer
    Division of Hematology and Oncology, Hospital of The University of Pennsylvania)

  • Nicolas Espagnolle

    (STROMALab, Université de Toulouse, CNRS ERL5311, EFS, INP-ENVT, Inserm U1031, UPS)

  • Jean-Christophe Pagès

    (STROMALab, Université de Toulouse, CNRS ERL5311, EFS, INP-ENVT, Inserm U1031, UPS)

  • Alice Carrier

    (Aix Marseille Université, CNRS, INSERM, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille)

  • Frédéric Bost

    (Inserm U1065, C3M, Team Cellular and Molecular Physiopathology of Obesity and Diabetes, Université Nice Côte d’Azur, Inserm)

  • Justine Bertrand-Michel

    (MetaToul-MetaboHUB, National Infrastructure of Metabolomics and Fluxomics)

  • Jérôme Tamburini

    (Translational Research Centre in Onco-hematology, Faculty of Medicine, University of Geneva
    Université de Paris, Institut Cochin, CNRS UMR8104, INSERM U1016)

  • Christian Récher

    (Cancer Research Center of Toulouse (CRCT), INSERM U1037, CNRS ERL5294, University of Toulouse
    Equipe labellisée, La Ligue contre le Cancer
    Service d’hématologie, Institut Universitaire du Cancer de Toulouse-Oncopole)

  • Sarah Bertoli

    (Cancer Research Center of Toulouse (CRCT), INSERM U1037, CNRS ERL5294, University of Toulouse
    Equipe labellisée, La Ligue contre le Cancer
    Service d’hématologie, Institut Universitaire du Cancer de Toulouse-Oncopole)

  • Véronique Mansat-De Mas

    (Cancer Research Center of Toulouse (CRCT), INSERM U1037, CNRS ERL5294, University of Toulouse
    Equipe labellisée, La Ligue contre le Cancer
    Laboratoire d’Hématologie, Institut Universitaire du Cancer de Toulouse-Oncopole)

  • Stéphane Manenti

    (Cancer Research Center of Toulouse (CRCT), INSERM U1037, CNRS ERL5294, University of Toulouse
    Equipe labellisée, La Ligue contre le Cancer)

  • Jean-Emmanuel Sarry

    (Cancer Research Center of Toulouse (CRCT), INSERM U1037, CNRS ERL5294, University of Toulouse
    Equipe labellisée, La Ligue contre le Cancer)

  • Carine Joffre

    (Cancer Research Center of Toulouse (CRCT), INSERM U1037, CNRS ERL5294, University of Toulouse
    Equipe labellisée, La Ligue contre le Cancer)

Abstract

Autophagy has been associated with oncogenesis with one of its emerging key functions being its contribution to the metabolism of tumors. Therefore, deciphering the mechanisms of how autophagy supports tumor cell metabolism is essential. Here, we demonstrate that the inhibition of autophagy induces an accumulation of lipid droplets (LD) due to a decrease in fatty acid β-oxidation, that leads to a reduction of oxidative phosphorylation (OxPHOS) in acute myeloid leukemia (AML), but not in normal cells. Thus, the autophagic process participates in lipid catabolism that supports OxPHOS in AML cells. Interestingly, the inhibition of OxPHOS leads to LD accumulation with the concomitant inhibition of autophagy. Mechanistically, we show that the disruption of mitochondria–endoplasmic reticulum (ER) contact sites (MERCs) phenocopies OxPHOS inhibition. Altogether, our data establish that mitochondria, through the regulation of MERCs, controls autophagy that, in turn finely tunes lipid degradation to fuel OxPHOS supporting proliferation and growth in leukemia.

Suggested Citation

  • Claudie Bosc & Nicolas Broin & Marjorie Fanjul & Estelle Saland & Thomas Farge & Charly Courdy & Aurélie Batut & Rawand Masoud & Clément Larrue & Sarah Skuli & Nicolas Espagnolle & Jean-Christophe Pag, 2020. "Autophagy regulates fatty acid availability for oxidative phosphorylation through mitochondria-endoplasmic reticulum contact sites," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17882-2
    DOI: 10.1038/s41467-020-17882-2
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    Cited by:

    1. Yun Seok Kim & Bongsub Ko & Da Jung Kim & Jihoon Tak & Chang Yeob Han & Joo-Youn Cho & Won Kim & Sang Geon Kim, 2022. "Induction of the hepatic aryl hydrocarbon receptor by alcohol dysregulates autophagy and phospholipid metabolism via PPP2R2D," Nature Communications, Nature, vol. 13(1), pages 1-19, December.

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