PMID- 32792483 OWN - NLM STAT- MEDLINE DCOM- 20200908 LR - 20220418 IS - 2041-1723 (Electronic) IS - 2041-1723 (Linking) VI - 11 IP - 1 DP - 2020 Aug 13 TI - Autophagy regulates fatty acid availability for oxidative phosphorylation through mitochondria-endoplasmic reticulum contact sites. PG - 4056 LID - 10.1038/s41467-020-17882-2 [doi] LID - 4056 AB - 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 beta-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. FAU - Bosc, Claudie AU - Bosc C AD - Cancer Research Center of Toulouse (CRCT), INSERM U1037, CNRS ERL5294, University of Toulouse, Toulouse, France. AD - Equipe labellisee, La Ligue contre le Cancer, Toulouse, France. FAU - Broin, Nicolas AU - Broin N AD - Cancer Research Center of Toulouse (CRCT), INSERM U1037, CNRS ERL5294, University of Toulouse, Toulouse, France. AD - Equipe labellisee, La Ligue contre le Cancer, Toulouse, France. FAU - Fanjul, Marjorie AU - Fanjul M AUID- ORCID: 0000-0001-8710-2488 AD - Cancer Research Center of Toulouse (CRCT), INSERM U1037, CNRS ERL5294, University of Toulouse, Toulouse, France. AD - Equipe labellisee, La Ligue contre le Cancer, Toulouse, France. FAU - Saland, Estelle AU - Saland E AD - Cancer Research Center of Toulouse (CRCT), INSERM U1037, CNRS ERL5294, University of Toulouse, Toulouse, France. AD - Equipe labellisee, La Ligue contre le Cancer, Toulouse, France. FAU - Farge, Thomas AU - Farge T AD - Cancer Research Center of Toulouse (CRCT), INSERM U1037, CNRS ERL5294, University of Toulouse, Toulouse, France. AD - Equipe labellisee, La Ligue contre le Cancer, Toulouse, France. FAU - Courdy, Charly AU - Courdy C AD - Cancer Research Center of Toulouse (CRCT), INSERM U1037, CNRS ERL5294, University of Toulouse, Toulouse, France. AD - Equipe labellisee, La Ligue contre le Cancer, Toulouse, France. FAU - Batut, Aurelie AU - Batut A AD - MetaToul-MetaboHUB, National Infrastructure of Metabolomics and Fluxomics, Toulouse, F-31077, France. FAU - Masoud, Rawand AU - Masoud R AD - Aix Marseille Universite, CNRS, INSERM, Institut Paoli-Calmettes, Centre de Recherche en Cancerologie de Marseille, Marseille, France. FAU - Larrue, Clement AU - Larrue C AD - Translational Research Centre in Onco-hematology, Faculty of Medicine, University of Geneva, 1211, Geneva, Switzerland. FAU - Skuli, Sarah AU - Skuli S AD - Cancer Research Center of Toulouse (CRCT), INSERM U1037, CNRS ERL5294, University of Toulouse, Toulouse, France. AD - Equipe labellisee, La Ligue contre le Cancer, Toulouse, France. AD - Division of Hematology and Oncology, Hospital of The University of Pennsylvania, Philadelphia, PA, USA. FAU - Espagnolle, Nicolas AU - Espagnolle N AUID- ORCID: 0000-0002-6321-6357 AD - STROMALab, Universite de Toulouse, CNRS ERL5311, EFS, INP-ENVT, Inserm U1031, UPS, Toulouse, France. FAU - Pages, Jean-Christophe AU - Pages JC AD - STROMALab, Universite de Toulouse, CNRS ERL5311, EFS, INP-ENVT, Inserm U1031, UPS, Toulouse, France. FAU - Carrier, Alice AU - Carrier A AD - Aix Marseille Universite, CNRS, INSERM, Institut Paoli-Calmettes, Centre de Recherche en Cancerologie de Marseille, Marseille, France. FAU - Bost, Frederic AU - Bost F AD - Inserm U1065, C3M, Team Cellular and Molecular Physiopathology of Obesity and Diabetes, Universite Nice Cote d'Azur, Inserm, Nice, France. FAU - Bertrand-Michel, Justine AU - Bertrand-Michel J AD - MetaToul-MetaboHUB, National Infrastructure of Metabolomics and Fluxomics, Toulouse, F-31077, France. FAU - Tamburini, Jerome AU - Tamburini J AD - Translational Research Centre in Onco-hematology, Faculty of Medicine, University of Geneva, 1211, Geneva, Switzerland. AD - Universite de Paris, Institut Cochin, CNRS UMR8104, INSERM U1016, F-75014, Paris, France. FAU - Recher, Christian AU - Recher C AUID- ORCID: 0000-0002-3332-4525 AD - Cancer Research Center of Toulouse (CRCT), INSERM U1037, CNRS ERL5294, University of Toulouse, Toulouse, France. AD - Equipe labellisee, La Ligue contre le Cancer, Toulouse, France. AD - Service d'hematologie, Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France. FAU - Bertoli, Sarah AU - Bertoli S AUID- ORCID: 0000-0003-1084-2781 AD - Cancer Research Center of Toulouse (CRCT), INSERM U1037, CNRS ERL5294, University of Toulouse, Toulouse, France. AD - Equipe labellisee, La Ligue contre le Cancer, Toulouse, France. AD - Service d'hematologie, Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France. FAU - Mansat-De Mas, Veronique AU - Mansat-De Mas V AD - Cancer Research Center of Toulouse (CRCT), INSERM U1037, CNRS ERL5294, University of Toulouse, Toulouse, France. AD - Equipe labellisee, La Ligue contre le Cancer, Toulouse, France. AD - Laboratoire d'Hematologie, Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France. FAU - Manenti, Stephane AU - Manenti S AD - Cancer Research Center of Toulouse (CRCT), INSERM U1037, CNRS ERL5294, University of Toulouse, Toulouse, France. AD - Equipe labellisee, La Ligue contre le Cancer, Toulouse, France. FAU - Sarry, Jean-Emmanuel AU - Sarry JE AUID- ORCID: 0000-0002-6704-2032 AD - Cancer Research Center of Toulouse (CRCT), INSERM U1037, CNRS ERL5294, University of Toulouse, Toulouse, France. jean-emmanuel.sarry@inserm.fr. AD - Equipe labellisee, La Ligue contre le Cancer, Toulouse, France. jean-emmanuel.sarry@inserm.fr. FAU - Joffre, Carine AU - Joffre C AUID- ORCID: 0000-0002-7551-356X AD - Cancer Research Center of Toulouse (CRCT), INSERM U1037, CNRS ERL5294, University of Toulouse, Toulouse, France. carine.joffre@inserm.fr. AD - Equipe labellisee, La Ligue contre le Cancer, Toulouse, France. carine.joffre@inserm.fr. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200813 PL - England TA - Nat Commun JT - Nature communications JID - 101528555 SB - IM MH - Animals MH - Autophagy/genetics/*physiology MH - Cell Line, Tumor MH - Cell Proliferation/genetics/physiology MH - Endoplasmic Reticulum/*genetics/*metabolism MH - Flow Cytometry MH - Humans MH - Leukemia/genetics/*metabolism MH - Leukemia, Myeloid, Acute/*metabolism/pathology MH - Lipid Metabolism/genetics/physiology MH - Lipogenesis/genetics/physiology MH - Mice MH - Mitochondria/genetics/*metabolism MH - Oxidation-Reduction MH - Oxidative Phosphorylation PMC - PMC7426880 COIS- The authors declare no competing interests. EDAT- 2020/08/15 06:00 MHDA- 2020/09/09 06:00 PMCR- 2020/08/13 CRDT- 2020/08/15 06:00 PHST- 2019/06/13 00:00 [received] PHST- 2020/07/22 00:00 [accepted] PHST- 2020/08/15 06:00 [entrez] PHST- 2020/08/15 06:00 [pubmed] PHST- 2020/09/09 06:00 [medline] PHST- 2020/08/13 00:00 [pmc-release] AID - 10.1038/s41467-020-17882-2 [pii] AID - 17882 [pii] AID - 10.1038/s41467-020-17882-2 [doi] PST - epublish SO - Nat Commun. 2020 Aug 13;11(1):4056. doi: 10.1038/s41467-020-17882-2.