Article

Life’s smile, death’s grin: vital functions of apoptosis-executing proteins

INSERM U-517, Faculty of Medicine and Pharmacy, 7 Boulevard Jeanne d'Arc, 21033 Dijon, France.
Current Opinion in Cell Biology (Impact Factor: 8.74). 01/2005; 16(6):639-46. DOI: 10.1016/j.ceb.2004.09.008
Source: PubMed

ABSTRACT 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.

Download full-text

Full-text

Available from: Guido Kroemer, May 24, 2015
1 Follower
 · 
125 Views
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    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 01/2012; 3(3):237-44.
  • Source
    • "A key player in cell death is caspase 3, onto which two major pathways converge (Levkau et al, 1998). Despite the wide acceptance of the importance of caspases in contributing to cell death, several forms have recently been shown to be activated in the context of nonlethal processes and differentiation pathways (Galluzzi et al, 2008; Garrido and Kroemer, 2004). For example, caspase 3 has been shown to be transiently activated during early antigen-driven expansion of CD8 + T cells in vivo without any cell death occurring (McComb et al, 2010). "
    [Show abstract] [Hide abstract]
    ABSTRACT: One of the hallmarks of stroke pathophysiology is the widespread death of many different types of brain cells. As our understanding of the complex disease that is stroke has grown, it is now generally accepted that various different mechanisms can result in cell damage and eventual death. A plethora of techniques is available to identify various pathological features of cell death in stroke; each has its own drawbacks and pitfalls, and most are unable to distinguish between different types of cell death, which partially explains the widespread misuse of many terms. The purpose of this review is to summarize the standard histopathological and immunohistochemical techniques used to identify various pathological features of stroke. We then discuss how these methods should be properly interpreted on the basis of what they are showing, as well as advantages and disadvantages that require consideration. As there is much interest in the visualization of stroke using noninvasive imaging strategies, we also specifically discuss how these techniques can be interpreted within the context of cell death.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 11/2011; 32(2):213-31. DOI:10.1038/jcbfm.2011.150 · 5.34 Impact Factor
  • Source
    • "Furthermore, there are an increasing number of studies in which classical cell death-related proteins are being discovered to have other roles during development under physiological conditions. For instance, Caspase-3 has been involved in cell fate decision during development (Garrido and Kroemer, 2004; Kuranaga, 2011; Kuranaga and Miura, 2007). Outside of the CNS, Bcl-X L has been implicated in the control of cell cycle through yet poorly understood mechanisms, in which cell cycle inhibitors are involved ( Janumyan et al., 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Understanding the developmental mechanisms governing dopaminergic neuron generation and maintenance is crucial for the development of neuronal replacement therapeutic procedures, like in Parkinson's disease (PD), but also for research aimed at drug screening and pharmacology. In the present chapter, we review the present situation using stem cells of different origins (pluripotent and multipotent) and summarize current manipulations of stem cells for the enhancement of dopaminergic neuron generation, focusing on the actions of Bcl-X(L). Bcl-X(L) not only enhances dopaminergic neuron survival but also augments the expression of key developmental and maintenance genes, and, through the lengthening of the cell cycle early during differentiation, regulates cell fate decisions, producing a net enhancement of neurogenesis. The relevance of these findings is discussed in the context of basic neurogenesis and also for the development of efficient cell therapy in PD.
    Vitamins & Hormones 01/2011; 87:175-205. DOI:10.1016/B978-0-12-386015-6.00029-9 · 1.78 Impact Factor