Organelle Cross-Talk in Apoptotic and Survival Pathways

Although glycogen synthase kinase-3 beta (GSK-3 β ) was originally named for its ability to phosphorylate glycogen synthase and regulate glucose metabolism, this multifunctional kinase is presently known to be a key regulator of a wide range of cellular functions. GSK-3 β is involved in modulating a variety of functions including cell signaling, growth metabolism, and various transcription factors that determine the survival or death of the organism. Secondary to the role of GSK-3 β in various diseases including Alzheimer’s disease, inﬂammation, diabetes, and cancer, small molecule inhibitors of GSK-3 β are gaining signiﬁcant attention. This paper is primarily focused on addressing the bifunctional or conﬂicting roles of GSK-3 β in both the promotion of cell survival and of apoptosis. GSK-3 β has emerged as an important molecular target for drug development. It is commonly believed that sustained elevations in the mitochondrial matrix Ca 2+ concentration are a major feature of the intracellular cascade of lethal events during cerebral ischemia. The physical association between the endoplasmic reticulum (ER) and mitochondria, known as the mitochondria-associated ER membrane (MAM), enables highly e ﬃ cient transmission of Ca 2+ from the ER to mitochondria under both physiological and pathological conditions. Molecular chaperones are well known for their protective e ﬀ ects during cerebral ischemia. It has been demonstrated recently that many molecular chaperones coexist with MAM and regulate the MAM and thus Ca 2+ concentration inside mitochondria. Here, we review recent research on cerebral ischemia and MAM, with a focus on molecular chaperones and ER-mitochondrial calcium transfer. Mitochondria participate in a variety of physiologic processes, such as ATP production, lipid metabolism, iron-sulfur cluster biogenesis, and calcium bu ﬀ ering. The morphology of mitochondria changes dynamically due to their frequent fusion and division in response to cellular conditions, and these dynamics are an important constituent of apoptosis. The discovery of large GTPase family proteins that regulate mitochondrial dynamics, together with novel insights into the role of mitochondrial fusion and ﬁssion in apoptosis, has provided important clues to understanding the molecular mechanisms of cellular apoptosis. In this paper, we brieﬂy summarize current knowledge of the role of mitochondrial dynamics in apoptosis and cell pathophysiology in mammalian cells. c , smac/DIABLO, HtrA2/omi). Mitochondrial ﬁssion facilitates these reactions (State I). In contrast, elongated but cristae-disrupted mitochondria (i.e., Drp1- and OPA1-double RNAi cells; Drp1-KO and OPA1 RNAi cells) exhibit a signiﬁcant delay only in the cytochrome c release in response to apoptotic stimuli, because of the absence of mitochondrial fragmentation. Of note, however, MOM targeting and oligomeric assembly of Bax and the release of the IMS-soluble Smac/DIABLO normally proceed (State II). State III: presumed MOM permeabilized state in the absence of both cristae disorganization and mitochondrial fragmentation. MOMP: mitochondrial outer membrane permeabilization. For several decades, apoptosis has taken center stage as the principal mechanism of programmed cell death (type I cell death) in mammalian tissues. Autophagic cell death (type II) is characterized by the massive accumulation of autophagic vacuoles in the cytoplasm of cells. The autophagic process is activated as an adaptive response to a variety of extracellular and intracellular stresses, including nutrient deprivation, hormonal or therapeutic treatment, pathogenic infection, aggregated and misfolded proteins, and damaged organelles. Increasing evidence indicates that autophagy is associated with a number of pathological processes, including cancer. The regulation of autophagy in cancer cells is complex since it can enhance cancer cell survival in response to certain stresses, while it can also act to suppress the initiation of cancer growth. This paper focused on recent advances regarding autophagy in cancer and the techniques currently available to manipulate autophagy. Cisplatin (cisPt) is a chemotherapy agent used as a treatment for several types of cancer. The main cytotoxic e ﬀ ect of cisplatin is generally accepted to be DNA damage. Recently, the mechanism by which cisPt generates the cascade of events involved in the apoptotic process has been demonstrated. In particular it has been shown that some organelles are cisPt target and are involved in cell death. This paper aims to describe the morphological and functional changes of the Golgi apparatus and lysosomes during apoptosis induced in neuronal rat cells (B50) by cisplatin. The results obtained show that the cellular organelles are the target of cisPt, so their damage can induce cell death.

Apoptosis and survival pathways are intimately connected signal transduction cascades that determine the fate of cells suffering from insults such as DNA damage, oxidative stress, intracellular Ca 2+ overload, mild excitotoxicity, accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER), and many others, or induced to autoelimination by extracellular signals. The apoptotic pathways, respectively, intrinsic or extrinsic, are executed through molecular signals travelling inside the cells. If the initial studies considered the nucleus, and specifically DNA, as both primary sensor and executioner of apoptosis, active roles of other intracellular organelles have been pointed out in the last two decades, identifying plasma membrane as the initiator of the extrinsic pathway and mitochondria as the pivot of the intrinsic pathway. In apoptosing cells, the outer membrane of mitochondria is permeabilized by the proapoptotic members of the Bcl-2 family, promoting the release of proapoptotic factors such as the primary and secondary activators of caspases (cytochrome c and SMAC/diablo, resp.). Stress signals, typically inducing the intrinsic apoptotic pathway, must be perceived by the damaged cells and translated into signals that promote mitochondria permeabilization, after which caspases are activated. This implies that other organelles participate in apoptotic signaling upstream to mitochondria involvement, acting as sensors of damage or signal transducers. Recently, a key role of the endoplasmic reticulum (ER) is emerging, consisting of the ability of amplifying or dampening the apoptotic signal prior to mitochondria involvement, through the establishment of active Ca 2+ fluxes that control the physical and functional interaction between mitochondria and ER. Also lysosomes participate to the intrinsic apoptotic signaling, and their dialogs with mitochondria have been described.
Other important examples of organelles cross-talk in apoptosis include nucleus-mitochondria exchange of proteins such as p53, which is main controller of the cell response to DNA damage. To date, the role of organelles other than mitochondria in perceiving and signaling cell damage, and the interrelation of the organelles during apoptotic signaling, are still poorly explored matters.
In this special issue dedicated to Organelle Cross-talk in Apoptotic and Survival Pathways, original research papers and review articles are collected with the aim of giving an impulse to this promising field of research on apoptosis and stimulating discussion between interdisciplinary readers. The paper written by Y.-B. Ouyang and R. G. Giffard describes ER-mitochondria cross-talk during cerebral ischemia. The authors precisely describe the chaperone machineries at both the ER and mitochondrion. Moreover, they contribute the new view that the chaperones organise not only the regulation of Ca 2+ signaling between these two organelles and control bioenergetics, cell survival, but also cell death decision.
In the paper entitled "Mitochondrial dynamics: functional link with apoptosis", written by H. Otera and K. Mihara, the readers are introduced to "intrinsic" apoptotic pathway in the context of regulation and physiologic significance of mitochondrial fusion and fission. The authors of this review underline also that the ER-mitochondria contact is involved in the regulation of mitochondrial energy, lipid metabolism, calcium signaling, and even in mitochondrial fission.
An important issue arising is the cross-talk of apoptosis with autophagy, a stress response pathway controlled by key intracellular regulators such as m-TOR, induced by insults or International Journal of Cell Biology conditions ranging from nutrient depletion, protein malfolding, or cell ageing. The paper written by H. Rikiishi focusing on the recent advances regarding autophagy in cancer and the techniques currently available to manipulate autophagy. The author of this paper provides a complete overview of the literature on molecular mechanism of autophagy and its cross-talk with apoptosis. Additionally, the author indicates the technical problems in the study of autophagy and suggest that new methods need to be developed to ensure progress in this area of investigation. Moreover, they highlight that the multifaceted nature of autophagy and its diverse cross-talk with other biological processes must be carefully considered when the autophagic system is targeted for anticancer benefits.
The paper entitled "Effects of cisplatin in neuroblastoma rat cells: damage to cellular organelles" written by G. Santin et al. provides the practical analysis of organelle cross-talk during cell death. The authors indicate that B50 neuroblastoma cells treated with cisplatin undergo apoptosis through organelles injury, and not only as a consequent of DNA damage, but also that cisplatin does not induce any autophagic process as alternative response to the treatment.
In conclusion, the studies collected in this issue effectively contribute to the general problem of organelles as target of cell damage versus transducer of the apoptotic signal.