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Molecular and Cellular Biology, February 2005, p. 1025-1040, Vol. 25, No. 3
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.3.1025-1040.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Inhibition of Macroautophagy Triggers Apoptosis{dagger}

Patricia Boya,1,{ddagger},§ Rosa-Ana González-Polo,1,{ddagger} Noelia Casares,1 Jean-Luc Perfettini,1 Philippe Dessen,1 Nathanael Larochette,1 Didier Métivier,1 Daniel Meley,2 Sylvie Souquere,3 Tamotsu Yoshimori,4 Gérard Pierron,3 Patrice Codogno,2 and Guido Kroemer1*

CNRS-UMR8125, Institut Gustave Roussy,1 Laboratoire Replication de l'ADN et Ultrastructure du Noyau, UPR-1983, and INSERM U504,3 Institut André Lwoff, Villejuif, France,2 National Institute of Genetics, Mishima, Japan4

Received 6 May 2004/ Returned for modification 8 June 2004/ Accepted 19 October 2004

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.

* Corresponding author. Mailing address: CNRS-UMR 8125, Institut Gustave Roussy, Pavillon de Recherche 1, 39 rue Camille-Desmoulins, F-94805 Villejuif, France. Phone: 33-1-42 11 60 46. Fax: 33-1-42 11 60 47. E-mail: kroemer{at}igr.fr.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} P.B. and R.-A.G.-P. contributed equally to this work.

§ Present address: Consejo Superior de Investigaciones Científicas, E-28040 Madrid, Spain.

Molecular and Cellular Biology, February 2005, p. 1025-1040, Vol. 25, No. 3
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.3.1025-1040.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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