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Mol. Cell. Biol. doi:10.1128/MCB.02116-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Drp1 Mediates Caspase-Independent Type III Cell Death in Normal and Leukemic Cells

Apoptose et Système Immunitaire, CNRS-URA 1961, Institut Pasteur, 25 rue du Dr. Roux. 75015 Paris, France; Centre de Recherche du CHUM, Hôpital Notre-Dame, Laboratoire d'Immunorégulation, 1560 Sherbrooke St East, Montréal, QC H2L 4M1, Canada; Service d'Hématologie Biologique, Groupe Hospitalier Pitie-Salpêtrière, Paris, France; Unitat de Neurobiologia Cellular, Departament de Ciencies Mediques Basiques, Facultat de Medicina, Lleida, Spain

^* To whom correspondence should be addressed. Email: susin{at}pasteur.fr.

	Abstract

Ligation of CD47 triggers caspase-independent programmed cell death (PCD) in normal and leukemic cells. Here, we characterize the morphological and biochemical features of this type of death and show that it displays the hallmarks of type III PCD. A molecular and biochemical approach has led us to identify a key mediator of this type of death: Dynamin-related protein 1 (Drp1). CD47 ligation induces Drp1 translocation from cytosol to mitochondria, a process controlled by chymotrypsin-like serine proteases. Once in mitochondria, Drp1 provokes an impairment of the mitochondrial electron transport chain, which results in _m dissipation, reactive oxygen species generation, and a drop in ATP levels. Surprisingly, neither the activation of the most representative pro-apoptotic members of the Bcl-2 family, such as Bax or Bak, nor the release of apoptogenic proteins AIF, cytochrome c, EndoG, Omi/HtrA2, or Smac/DIABLO from mitochondria to cytosol is observed. Responsiveness of cells to CD47 ligation increases following Drp1 overexpression, while Drp1 downregulation confers resistance to CD47-mediated death. Importantly, in B-chronic lymphocytic leukemia cells, mRNA levels of Drp1 strongly correlate with death sensitivity. Thus, this previously unknown mechanism controlling caspase-independent type III PCD may provide the basis for novel therapeutic approaches to overcome apoptotic avoidance in malignant cells.