Life’s smile, death’s grin: Vital functions of apoptosis-executing proteins. Curr Opin Cell Biol

INSERM U-517, Faculty of Medicine and Pharmacy, 7 Boulevard Jeanne d'Arc, 21033 Dijon, France.
Current Opinion in Cell Biology (Impact Factor: 8.47). 01/2005; 16(6):639-46. DOI: 10.1016/
Source: PubMed


Apoptosis is executed by caspases as well as caspase-independent death effectors. Caspases are expressed as inactive zymogens in virtually all animal cells and are activated in cells destined to undergo apoptosis. However, there are many examples where caspase activation is actually required for cellular processes not related to cell death, namely terminal differentiation, activation, proliferation, and cytoprotection. Several caspase-independent death effectors including apoptosis-inducing factor, endonuclease G and a serine protease (Omi/HtrA2) are released from the mitochondrial intermembrane space upon permeabilization of the outer membrane. Such proteins also have important roles in cellular redox metabolism and/or mitochondrial biogenesis. As a general rule, it thus appears that cell-death-relevant proteins, especially those involved in the core of the executing machinery, have a dual function in life and death. This has important implications for pathophysiology. The fact that the building blocks of the apoptotic machinery have normal functions not related to cell death may mean that essential parts of the apoptotic executioner cannot be lost and thus reduces the possibility of oncogenic mutations that block the apoptotic program. Moreover, therapeutic suppression of unwarranted cell death must be designed to target only the lethal (and not the vital) role of death effectors.


Available from: Guido Kroemer, May 24, 2015
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    • "In contrast, apoptosis mediated by the intrinsic pathway is characterized by alterations of the inner mitochondrial membrane, that in turn leads to the loss of mitochondrial membrane potential (Δψm).1–4,54 The loss of Δψm leads to the release of the pro-apoptotic proteins, which are characteristic of mitochondrial damage; these molecules include cytochrome c (cyt c), Smac/DIABLO, and the serine protease HtrA2/Omi56,57 apoptosis inducing factors (AIF) endonuclease G and caspase-activated deoxyribonuclease (CAD).54 However, the release of these proteins leads to the activation of caspases such as caspase-9 and caspase-3, whose activation is associated with the loss of Δψm;1,2 the mechanism by which the released cyt c mediates apoptosis is regulated by its binding to both Apaf-1 and pro-caspase-9 to form a protein complex known as the apoptosome.58,59 "
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    ABSTRACT: Both apoptosis and autophagy are highly conserved processes that besides their role in the maintenance of the organismal and cellular homeostasis serve as a main target of tumor therapeutics. Although their important roles in the modulation of tumor therapeutic strategies have been widely reported, the molecular actions of both apoptosis and autophagy are counteracted by cancer protective mechanisms. While apoptosis is a tightly regulated process that is implicated in the removal of damaged or unwanted cells, autophagy is a cellular catabolic pathway that is involved in lysosomal degradation and recycling of proteins and organelles, and thereby is considered an important survival/protective mechanism for cancer cells in response to metabolic stress or chemotherapy. Although the relationship between autophagy and cell death is very complicated and has not been characterized in detail, the molecular mechanisms that control this relationship are considered to be a relevant target for the development of a therapeutic strategy for tumor treatment. In this review, we focus on the molecular mechanisms of apoptosis, autophagy, and those of the crosstalk between apoptosis and autophagy in order to provide insight into the molecular mechanisms that may be essential for the balance between cell survival and death as well as their role as targets for the development of novel therapeutic approaches.
    Journal of Cell Death 08/2013; 6(1):37-55. DOI:10.4137/JCD.S11034
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    • "Evidence for this dual-function in life and death is provided by Garrido and Kroemer [58] who report that most pro-apoptosis proteins also have essential metabolic functions distinct from apoptosis. For example, caspase activation is required for cellular processes unrelated to cell death, such as terminal differentiation, proliferation and cytoprotection [59]. "
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    ABSTRACT: It is more than 25 years since the first report that a protozoan parasite could die by a process resulting in a morphological phenotype akin to apoptosis. Since then these phenotypes have been observed in many unicellular parasites, including trypanosomatids and apicomplexans, and experimental evidence concerning the molecular pathways that are involved is growing. These observations support the view that this form of programmed cell death is an ancient one that predates the evolution of multicellularity. Here we review various hypotheses that attempt to explain the origin of apoptosis, and look for support for these hypotheses amongst the parasitic protists as, with the exception of yeast, most of the work on death mechanisms in unicellular organisms has focussed on them. We examine the role that addiction modules may have played in the original eukaryote cell and the part played by mitochondria in the execution of present day cells, looking for examples from Leishmania spp. Trypanosoma spp. and Plasmodium spp. In addition, the expanding knowledge of proteases, nucleases and other molecules acting in protist execution pathways has enabled comparisons to be made with extant Archaea and bacteria and with biochemical pathways that evolved in metazoans. These comparisons lend support to the original sin hypothesis but also suggest that present-day death pathways may have had multifaceted beginnings.
    Parasites & Vectors 04/2013; 6(1):108. DOI:10.1186/1756-3305-6-108 · 3.43 Impact Factor
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    • "Mitochondria are at the crossroads of several crucial activities including ATP generation via oxidative phosphorylation; the biosynthesis of heme, pyrimidines and steroids, calcium and iron homeostasis, and programmed cell death [26] [27]. By releasing several proteins that incite programmed cell death, mitochondria are thought to act as " executioners " in apoptosis [28]. Mitochondrial defects, once known to cause only rare severe metabolic and neurological diseases, are now believed to contribute to a wide range of disorders, including common disorders such as hypertension, diabetes, cancers, and neurodegenerative disorders [12] [13] [14]. "
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    ABSTRACT: A growing body of evidence suggests that mitochondrial dysfunction is associated with oxidative stress and impaired differentiation and invasion of trophoblasts, both of which have been related to preeclampsia pathogenesis. However, studies that examined circulating mitochondrial DNA (mtDNA) copy number in relation to preeclampsia are limited. Therefore, we examined association of maternal whole blood mtDNA copy number (a novel biomarker of systemic mitochondrial dysfunction) with the odds of preeclampsia. This case-control study was comprised of 144 preeclampsia cases and 407 normotensive controls. Real-time quantitative polymerase chain reaction (PCR) was used to assess the relative copy number of mtDNA in maternal whole blood samples collected at delivery. Logistic regression procedures were used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI). Median mtDNA copy number was significantly higher among preeclamptic women compared with controls (271.5 vs. 239.3, Mann-Whitney U test p-value <0.001). There was evidence of a linear trend in higher odds of preeclampsia with increasing quartiles of mtDNA copy number (P for trend=0.03) after controlling for confounders. The adjusted ORs for the successive quartiles of mtDNA copy number, compared with the referent (first quartile) were 1.30 (95%CI 0.66-2.56), 1.93 (95%CI 1.02-3.67) and 1.86 (95%CI 1.00-3.48). Our findings suggest that maternal mitochondrial dysfunction may contribute to the pathogenesis of preeclampsia. However, replication in prospective studies is needed to further investigate this relationship.
    International Journal of Molecular Epidemiology and Genetics 10/2012; 3(3):237-44. · 1.30 Impact Factor
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