Current Molecular Medicine - Volume 8, Issue 2, 2008

Cell death under physiological and pathological conditions occurs with diverse morphological patterns, suggesting highly complex cell death mechanisms (Fig. 1). Apoptosis is a conserved cell death form essential for normal development and tissue homeostasis in multicellular organisms. Although apoptosis presumably participates in the development of all cell lineages, aberrations in the expression of pro- or anti-apoptotic proteins have been implicated in the initiation of a variety of human diseases, including autoimmunity, immunodeficiency, cancer, neurodegenerative diseases and many others. Several signaling pathways have been implicated in the regulation of apoptosis, including the extrinsic death receptor pathway, and the intrinsic mitochondrial pathway, which depends on activation of cysteine proteases of the caspase family for the execution of apoptosis. In the apoptosis pathway, the BCL-2 family of proteins is located upstream at organelle membranes, controlling the activation of downstream caspases. Although apoptosis is the prevalent form of programmed cell death (PCD) employed to control cell viability and homeostasis during development, increasing evidence indicates that alternative PCD pathways exist that may be particularly relevant under pathological conditions. Necrosis, also referred to as accidental cell death, is characterized by rapid swelling of the dying cell, rupture of the plasma membrane, and release of the cytoplasmic content to the cell environment. Despite the profound effects of necrosis-like cell death in pathological conditions such as stroke, ischemia, and several neurodegenerative diseases, the molecular mechanisms underlying necrotic cell death are poorly understood. Necrosis has traditionally been defined as an unregulated, accidental cell-death process that occurs under conditions of cellular injury related to the loss of ion homeostasis and drastic decreases in ATP levels. In recent years, however, an increasing number of reports indicate that cell death with necrotic features can occur under normal physiological conditions during development by regulated and controlled mechanisms. Cell death is often associated with the presence of numerous cytoplasmic autophagic vacuoles of lysosomal origin. Lysosomes have been referred to as “suicide bags” because they contain several unspecific digestive enzymes that, upon release into the cytosol, cause autolysis and cell death. Autophagy, also defined as type II PCD, acts as a critical survival response under starvation conditions in which the degradation of intracellular proteins and organelles provides a source of amino acids during poor nutritional conditions. Intracellular components can be delivered to lysosomes for degradation by three different mechanisms known as macroautophagy, microautophagy and chaperone- mediated autophagy. Lysosome-mediated cell death has been linked to the apoptotic pathway through alterations in mitochondrial function, but its actual role as a cell death effecter is actively debated. The hallmark of autophagy is the formation of double-membrane bound autophagosomes. Autophagosomes fuse with lysosomes to form autophagolysosomes, where intracellular components are degraded. Autophagy is a highly regulated process with complex steps controlled by a group of autophagic related genes of the atg family which function in diverse processes including development, cell differentiation, tissue remodeling, immunity, host-to-pathogen response and cell death/survival under stress conditions. Members of the BCL-2 protein family have been recently shown to modulate autophagy through the formation of distinct regulatory protein complexes, suggesting a direct link between autophagy and apoptosis. This special edition of the Current Molecular Medicine contains a selection of reviews focused on different aspects of apoptosis, necrosis and autophagy to provide an overview of the relevance of these stress pathways in many physiological and pathological conditions. In this volume of Curr. Mol. Med., Guido Kroemer and Maria Isabel Colombo give a comprehensive summary of regulatory mechanisms governing autophagy, highlighting its emerging function in both immune response and the intimate connections with cell death. Anthony Letai and Gordon Shore discuss recent data highlighting the relevance of the BCL-2 protein family in disease conditions such as cancer and the possible therapeutic benefits of targeting the pathway with small molecules. To complement this view, Kerstin Reimers describe an uncharacterized family of conserved regulators of cell death, the BAX-inhibitor 1 family, and its possible role in cancer. The inability of a cell to adapt to prolonged perturbations of organelle homeostasis ends with the activation of specific cell death pathways. Accumulation of abnormal protein aggregates composed of misfolded proteins is a common characteristic of many neurological diseases, engaging organelle stress responses. Here we discuss recent data about the involvement of apoptosis and autophagy in neurodegeneration. To complement this view, Dale Bredesen presents a broad view about the role of cell death in neurological disorders. Jean- Claude Martinou and Rosario Rizzuto prepared a deep summary of the involvement of mitochondria in calcium homeostasis and apoptosis, and the relevance of fission/fusion events in cell death and disease conditions. Finally, Andrew Quest, Andres Stutzin and Peter Vandenabeele uncover the molecular regulation of necrosis-like cell death and its role in diverse pathologies. With these set of specialized reviews we aim to provide a comprehensive view of the current understanding of cell death pathways and adaptive reactions to cellular stress. A special emphasis is given on the possible therapeutic benefits of targeting the aforementioned pathways in disease conditions.........

Macroautophagy (commonly referred to as autophagy) is the process by which intact organelles and/or large portions of the cytoplasm are engulfed within double-membraned autophagic vacuoles for degradation. Whereas basal levels of autophagy ensure the physiological turnover of old and damaged organelles, the massive accumulation of autophagic vacuoles may represent either an alternative pathway of cell death or an ultimate attempt for cells to survive by adapting to stress. The activation of the autophagic pathway beyond a certain threshold may promote cell death directly, by causing the collapse of cellular functions as a result of cellular atrophy (autophagic, or type II, cell death). Alternatively, autophagy can lead to the execution of apoptotic (type I) or necrotic (type III) cell death programs, presumably via common regulators such as proteins from the Bcl-2 family. On the other hand, limited self-eating can provide cells with metabolic substrates to meet their energetic demands under stressful conditions, such as nutrient deprivation, or favor the selective elimination of damaged (and potentially dangerous) organelles. In these instances, autophagy operates as a pro-survival mechanism. The coordinate regulation of these opposite effects of autophagy relies upon a complex network of signal transducers, most of which also participate in non-autophagic signaling cascades. Thus, autophagy occupies a crucial position within the cell's metabolism, and its modulation may represent an alternative therapeutic strategy in several pathological settings including cancer and neurodegeneration. Here, we present a general outline of autophagy followed by a detailed analysis of organelle-specific autophagic pathways and of their intimate connections with cell death.

Autophagy is a bulk cytosolic degradative process which in the last few years has become a key pathway for the advancement of molecular medicine. Autophagy (cellular self-eating) has several implications in human disorders involving accumulation of cytosolic protein aggregates such as Alzheimer, Parkinson, Huntington diseases, as well as in myopathies caused by deficient lysosomal functions and in cancer. Moreover, autophagy affects intracellular microorganism lifespan, acting either as a cellular defense mechanism or, on the contrary, promoting pathogen replication. Furthermore, autophagy also participates in antigen presentation, as a part of the adaptive immune response. Therefore, autophagy association with cell survival or cell death would depend on cell nutrition conditions, presence of cell intruders, and alterations in oncogene or suppressor gene expression. In this review we will focus on the wide spectra of disease-related topics where autophagy is involved, particularly, in those processes concerning microorganism infections.

Like many proteins, function and abundance of Bcl-2 family proteins are influenced by posttranslational modifications. These modifications include phosphorylation, proteolytic cleavage, ubiquitination, and proteosomal degradation. These modifications, depending on cellular context and the proteins involved, can result either in a promotion of inhibition of apoptosis. Many of these modifications are governed by the activity of enzymes. As modulation of enzymatic activity can be achieved fairly efficiently using small molecules, understanding the effects of posttranslational modifications may allow for the therapeutic inhibition or promotion of apoptosis.

In the complex interplay that allows different signals to be decoded into activation of cell death, calcium (Ca2+) plays a significant role. In all eukaryotic cells, the cytosolic concentration of Ca2+ ions ([Ca2+]c) is tightly controlled by interactions among transporters, pumps, channels and binding proteins. Finely tuned changes in [Ca2+]c modulate a variety of intracellular functions ranging from muscular contraction to secretion, and disruption of Ca2+ handling leads to cell death. In this context, Ca2+ signals have been shown to affect important checkpoints of the cell death process, such as mitochondria, thus tuning the sensitivity of cells to various challenges. In this contribution, we will review (i) the evidence supporting the involvement of Ca2+ in the three major process of cell death: apoptosis, necrosis and autophagy (ii) the complex signaling interplay that allows cell death signals to be decoded into mitochondria as messages controlling cell fate.

Mitochondria are essential organelles of all eukaryotic cells that play a key role in several physiological processes and are involved in the pathology of many diseases. These organelles form a highly dynamic network, which results from continuous fusion and fission processes. Importance of these processes is underlined by inherited human diseases caused by mutations in two mitochondrial pro-fusion genes: Charcot-Marie- Tooth disease, caused by mutations in Mitofusin 2 gene and ADOA due to mutations in OPA1. During apoptosis, the mitochondrial network is disintegrated and the outer mitochondrial membrane permeabilized, which results in the release of several apoptogenic proteins, including cytochrome c. Although modulating mitochondrial fusion and fission machineries has been reported to influence the apoptotic response to various stimuli, it is still unclear whether fission is absolutely required for apoptosis. In this review, we present the latest progress in the field of mitochondrial dynamics with a particular emphasis on its implication in apoptosis and in diseases.

Accumulating evidence suggests that Mcl-1 plays a critical pro-survival role in the development and maintenance of both normal and malignant tissues. Regulation of Mcl-1 expression occurs at multiple levels, allowing for either the rapid induction or elimination of the protein in response to different cellular events. This suggests that Mcl-1 can play an early role in response to signals directing either cell survival or cell death. Deregulation of pathways regulating Mcl-1 that result in its over-expression likely contribute to a cell's inability to properly respond to death signals possibly leading to cell immortalization and tumorigenic conversion. Correspondingly, Mcl-1 has been shown to be up-regulated in numerous hematological and solid tumor malignancies. Moreover, this up-regulation appears to be a factor in the resistance of some cancer types to conventional cancer therapies. Mechanisms that abrogate the pro-survival function of Mcl-1 either by diminishing its levels or inactivating its functional BH3 groove have shown promise for the combinational treatment with existing cancer therapies and as single agents in certain malignancies. Here we review the various pathways that regulate Mcl-1 expression and describe agents that are currently under development to modulate Mcl-1 activity for therapeutic benefit in oncology.

The signaling pathways that determine the fate of a cell regarding death or survival depend on a large number of regulatory proteins. The Bax Inhibitor-1 (BI-1) family is a highly preserved family of small transmembrane proteins located mostly in the endoplasmic reticulum (ER). Although most members of this family are still not characterized an antiapoptotic effect has been described for BI-1, Lifeguard (LFG), and the Golgi anti-apoptotic protein (GAAP). The cytoprotective activity has been associated to the control of ion homeostasis and ER stress but includes other cell death stimuli as well. Recent data describes multiple interactions between the proteins of the BI-1 family and the Bcl-2 family either stimulating the antiapoptotic function of Bcl-2 or inhibiting the proapoptotic effect of Bax. The potent cell death suppression makes this protein family an interesting target for the development of new drugs and gene therapeutic approaches for diseases caused by apoptotic dysregulation, such as cancer.