Inhibition of macroautophagy triggers apoptosis

Patricia Boya, Rosa Ana González-Polo, Noelia Casares, Jean Luc Perfettini, Philippe Dessen, Nathanael Larochette, Didier Métivier, Daniel Meley, Sylvie Souquere, Tamotsu Yoshimori, Gérard Pierron, Patrice Codogno, Guido Kroemer

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    Résumé

    Mammalian cells were observed to die under conditions in which nutrients were depleted and, simultaneously, macroautophagy was inhibited either genetically (by a small interfering RNA targeting Atg5, Atg6/Beclin 1-1, Atg10, or Atg12) or pharmacologically (by 3-methyladenine, hydroxychloroquine, bafilomycin A1, or monensin). Cell death occurred through apoptosis (type 1 cell death), since it was reduced by stabilization of mitochondrial membranes (with Bcl-2 or vMIA, a cytomegalovirus-derived gene) or by caspase inhibition. Under conditions in which the fusion between lysosomes and autophagosomes was inhibited, the formation of autophagic vacuoles was enhanced at a preapoptotic stage, as indicated by accumulation of LC3-II protein, ultrastructural studies, and an increase in the acidic vacuolar compartment. Cells exhibiting a morphology reminiscent of (autophagic) type 2 cell death, however, recovered, and only cells with a disrupted mitochondrial transmembrane potential were beyond the point of no return and inexorably died even under optimal culture conditions. All together, these data indicate that autophagy may be cytoprotective, at least under conditions of nutrient depletion, and point to an important cross talk between type 1 and type 2 cell death pathways.

    langue originaleAnglais
    Pages (de - à)1025-1040
    Nombre de pages16
    journalMolecular and Cellular Biology
    Volume25
    Numéro de publication3
    Les DOIs
    étatPublié - 1 janv. 2005

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