Article

Inhibition of Macroautophagy Triggers Apoptosis

CNRS-UMR 8125, Institut Gustave Roussy, Pavillon de Recherche 1, 39 rue Camille-Desmoulins, F-94805 Villejuif, France. .
Molecular and Cellular Biology (Impact Factor: 4.78). 03/2005; 25(3):1025-40. DOI: 10.1128/MCB.25.3.1025-1040.2005
Source: PubMed

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.

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