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Abstract
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.
SUPPLEMENTAL MATERIAL
Supplemental material for this article may be found at http://mcb.asm.org/.
ACKNOWLEDGMENTS
We thank Jennifer Lippincott-Schwartz (Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Md.), Victor Goldmacher (ImmunoGen, Inc., Cambridge, Mass.), Stanley J. Korsmeyer (Harvard Medical School, Boston, Mass.), and Norma W. Andrews (Section of Microbial Pathogenesis and Department of Cell Biology, Yale University School of Medicine, New Haven, Conn.) for reagents; Yann Lecluse (IGR, Villejuif, France) for cell sorting; Ana-Maria Cuervo (Albert Einstein College of Medicine, Bronx, N.Y.) for helpful discussion; Patrick Fitze (Laboratory of Ecology, University Pierre and Marie Curie, Paris, France) for statistical advice; and Abdelali Jalil (Institut Gustave Roussy, Villejuif, France) for confocal microscopy.
This work has been supported by a special grant from the LNC as well as grants from the ANRS and the European Commission (QLK3-CT-2002-01956 to G.K.). P.B. received a fellowship from the European Commission (MCFI-2000-00943), as did R.-A.G.-P. (FP6-2002-5000698); N.C. and J.-L.P. received grants from the FRM and the ANRS, respectively.