Necrotic cell death: From reversible mitochondrial uncoupling to irreversible lysosomal permeabilization

被引:24
作者
Giusti, Corinne [1 ,2 ,3 ,4 ]
Luciani, Marie-Francoise [1 ,2 ,3 ,4 ]
Klein, Gerard [5 ,6 ]
Aubry, Laurence [5 ,6 ]
Tresse, Emilie [1 ,2 ,3 ,4 ]
Kosta, Artemis [1 ,2 ,3 ,4 ]
Golstein, Pierre [1 ,2 ,3 ,4 ]
机构
[1] Aix Marseille Univ, Fac Sci Luminy, CIML, F-13288 Marseille, France
[2] INSERM U631, F-13288 Marseille, France
[3] CNRS, UMR6102, F-13288 Marseille, France
[4] CEA, iRTSV, DSV, Lab Biochim Biophys Syst Integres, F-38054 Grenoble, France
[5] CNRS, UMR5092, LBBSI, F-38054 Grenoble, France
[6] Univ Grenoble 1, F-38000 Grenoble, France
关键词
Necrotic cell death; Mitochondria; Lysosomes; Dictyostelium; ISCHEMIC NEURONAL DEATH; CYCLOPHILIN-D; APOPTOSIS; NECROSIS; AUTOPHAGY; DICTYOSTELIUM; TRANSITION; CALPAIN; NEURODEGENERATION; PROTEASES;
D O I
10.1016/j.yexcr.2008.09.028
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Dicryostelium atg1- mutant cells provide an experimentally and genetically favorable model to study necrotic cell death (NCD) with no interference from apoptosis or autophagy. In such cells subjected to starvation and CAMP, induction by the differentiation-inducing factor DIF or by classical uncouplers led within minutes to mitochondrial uncoupling, which causally initiated NCD. We now report that (1) in this model, NCD included a mitochondrial-lysosomal cascade of events, (2) mitochondrial uncoupling and therefore initial stages of death showed reversibility for a surprisingly long time, (3) subsequent lysosomal permeabilization could be demonstrated using Lysosensor blue, acridin orange, Texas red-dextran and cathepsin B substrate, (4) this lysosomal permeabilization was irreversible, and (5) the presence of the uncoupler was required to maintain mitochondrial lesions but also to induce lysosomal lesions, suggesting that signaling from mitochondria to lysosomes must be sustained by the continuous presence of the uncoupler. These results further characterized the NCD pathway in this priviledged model, contributed to a definition of NCD at the lysosomal level, and suggested that in mammalian NCD even late reversibility attempts by removal of the inducer may be of therapeutic interest. (C) 2008 Elsevier Inc. All rights reserved.
引用
收藏
页码:26 / 38
页数:13
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