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

Claudie Bosc, Nicolas Broin, Marjorie Fanjul, Estelle Saland, Thomas Farge, Charly Courdy, Aurélie Batut, Rawand Masoud, Clément Larrue, Sarah Skuli, Nicolas Espagnolle, Jean-Christophe Pagès, Alice Carrier, Frédéric Bost, Justine Bertrand-Michel, Jérôme Tamburini, Christian Récher, Sarah Bertoli, Véronique Mansat- De Mas, Stéphane Manenti, Jean-Emmanuel Sarry () and Carine Joffre ()
Additional contact information
Claudie Bosc: Cancer Research Center of Toulouse (CRCT), INSERM U1037, CNRS ERL5294, University of Toulouse
Nicolas Broin: Cancer Research Center of Toulouse (CRCT), INSERM U1037, CNRS ERL5294, University of Toulouse
Marjorie Fanjul: Cancer Research Center of Toulouse (CRCT), INSERM U1037, CNRS ERL5294, University of Toulouse
Estelle Saland: Cancer Research Center of Toulouse (CRCT), INSERM U1037, CNRS ERL5294, University of Toulouse
Thomas Farge: Cancer Research Center of Toulouse (CRCT), INSERM U1037, CNRS ERL5294, University of Toulouse
Charly Courdy: Cancer Research Center of Toulouse (CRCT), INSERM U1037, CNRS ERL5294, University of Toulouse
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
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
Christian Récher: Cancer Research Center of Toulouse (CRCT), INSERM U1037, CNRS ERL5294, University of Toulouse
Sarah Bertoli: Cancer Research Center of Toulouse (CRCT), INSERM U1037, CNRS ERL5294, University of Toulouse
Véronique Mansat- De Mas: Cancer Research Center of Toulouse (CRCT), INSERM U1037, CNRS ERL5294, University of Toulouse
Stéphane Manenti: Cancer Research Center of Toulouse (CRCT), INSERM U1037, CNRS ERL5294, University of Toulouse
Jean-Emmanuel Sarry: Cancer Research Center of Toulouse (CRCT), INSERM U1037, CNRS ERL5294, University of Toulouse
Carine Joffre: Cancer Research Center of Toulouse (CRCT), INSERM U1037, CNRS ERL5294, University of Toulouse

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17882-2

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