The calcium ion has long been known to play an important role in cell death regulation. Hence, necrotic cell death was early associated with intracellular Ca2+ overload, leading to mitochondrial ...permeability transition and functional collapse. Subsequent characterization of the signaling pathways in apoptosis revealed that Ca2+/calpain was critically involved in the processing of the mitochondrially localized, Apoptosis Inducing Factor. More recently, the calcium ion has been demonstrated to play important regulatory roles also in other cell death modalities, notably autophagic cell death and anoikis. In this review, we summarize current knowledge about the mechanisms involved in Ca2+ regulation of these various modes of cell death with a focus on the importance of the mitochondria.
•The interaction between the different forms of cell death is complex and still a matter of debate.•Mitochondria play a crucial role in several cell death modalities and in the cross-talk between them.•The Ca2+ ion is critically involved in both the initiation and effectuation of various modes of cell death.
Caspases are an evolutionary conserved family of cysteine-dependent proteases that are involved in many vital cellular processes including apoptosis, proliferation, differentiation and inflammatory ...response. Dysregulation of caspase-mediated apoptosis and inflammation has been linked to the pathogenesis of various diseases such as inflammatory diseases, neurological disorders, metabolic diseases, and cancer. Multiple caspase inhibitors have been designed and synthesized as a potential therapeutic tool for the treatment of cell death-related pathologies. However, only a few have progressed to clinical trials because of the consistent challenges faced amongst the different types of caspase inhibitors used for the treatment of the various pathologies, namely an inadequate efficacy, poor target specificity, or adverse side effects. Importantly, a large proportion of this failure lies in the lack of understanding various caspase functions. To overcome the current challenges, further studies on understanding caspase function in a disease model is a fundamental requirement to effectively develop their inhibitors as a treatment for the different pathologies. Therefore, the present review focuses on the descriptive properties and characteristics of caspase inhibitors known to date, and their therapeutic application in animal and clinical studies. In addition, a brief discussion on the achievements, and current challenges faced, are presented in support to providing more perspectives for further development of successful therapeutic caspase inhibitors for various diseases.
Oxidative (reactive oxygen species ROS) and nitrosative (reactive nitrogen species RNS) stress affects many physiological processes, including survival and death. Although high levels of ROS/RNS ...mainly causes cell death, low levels of free radicals directly modulate the activities of transcriptional factors, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), p53, and nuclear factor (erythroid-derived) 2-like (Nrf2), and regulate numerous protein kinase cascades that participate in the regulation of the cross talk between autophagy and apoptosis.
Low levels of ROS modify Atg4 and high mobility group box 1 (HMGB1) proteins, activate AMP-activated protein kinase (AMPK) and apoptosis signal-regulating kinase/c-Jun N-terminal kinase (JNK) pathways, or transactivate various proteins that could upregulate autophagy, leading to reductions in apoptosis. Transactivation of antioxidant genes blocks apoptosis and serves as a feedback loop to reduce autophagy. Free radicals could also activate protein kinase B (PKB, or Akt), preventing both autophagy and apoptosis. Stimulation of nitric oxide formation causes S-nitrosylation of several kinases, including JNK1 and IκB kinase β, which blocks autophagy and could promote apoptosis. However, S-nitrosylation of some proapoptotic proteins could block apoptosis.
Endoplasmic reticulum and mitochondria are the main sources of free radicals, which play an essential role in the regulation of apoptosis and autophagy. Oxidation of cardiolipin promotes cytochrome c release and apoptosis that potentially could be inhibited by autophagic clearance of damaged mitochondria. Elimination of damaged mitochondria reduces ROS accumulation, creating a feedback loop that causes inhibition of autophagy. Low levels of RNS could inhibit fission of mitochondria, which would block their degradation by autophagy and spare cells from apoptosis.
Understanding of mechanisms that regulate the cross talk between cell fates is essential for discovery of therapeutic tools in the strenuous fight against various disorders, including neurodegeneration and cancer.
Abstract Research during the past several decades has provided convincing evidence for a crucial role of the Ca2+ ion in cell signaling. Hence, intracellular Ca2+ transients have been implicated in ...most aspects of cell physiology, including gene transcription, cell cycle regulation and cell proliferation. Further, the Ca2+ ion has been found to also play an important role in cell death regulation. Thus, necrotic cell death was early associated with intracellular Ca2+ overload, and multiple functions in the apoptotic process have subsequently been found to be governed by Ca2+ signaling. More recently, other modes of cell death, notably anoikis and autophagic cell death, have been demonstrated to also be modulated by Ca2+ transients. Characteristics, interrelationship and mechanisms involved in Ca2+ regulation of these cell death modalities are discussed in this review.
Autophagy is an evolutionarily conserved process whereby damaged and redundant components of the cell are degraded in structures called autophagolysosomes. Currently, three main types of autophagy ...are recognized: macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). However, we still know little about some specific types of autophagy that are linked to various intracellular compartments and their roles in the physiology of the whole organism and connections to various diseases. Here, we aim to shed light on the latest insights on and mechanisms of several selective forms of autophagy.
The evolutionarily conserved process for the elimination of damaged and redundant components in cells is known as autophagy. Currently three forms of autophagy are described: macroautophagy, microautophagy, and chaperone-mediated autophagy.Recent advances in biochemistry and cell biology have revealed the selectivity of autophagy toward the various intracellular compartments. These selective types of autophagy are essential to ensure normal functioning of the cell.Dysregulation of autophagy and its selective types can cause numerous diseases, including neurodegeneration, microbial infections, and cancer.Understanding the molecular mechanisms of selective types of autophagy will help in the development of new compounds and therapeutic strategies to fight a wide spectrum of diseases.
The members of the Bcl-2 family are the central regulators of various cell death modalities. Some of these proteins contribute to apoptosis, while others counteract this type of programmed cell ...death, thus balancing cell demise and survival. A disruption of this balance leads to the development of various diseases, including cancer. Therefore, understanding the mechanisms that underlie the regulation of proteins of the Bcl-2 family is of great importance for biomedical research. Among the members of the Bcl-2 family, antiapoptotic protein Mcl-1 is characterized by a short half-life, which renders this protein highly sensitive to changes in its synthesis or degradation. Hence, the regulation of Mcl-1 is of particular scientific interest, and the study of Mcl-1 modulators could aid in the understanding of the mechanisms of disease development and the ways of their treatment. Here, we summarize the present knowledge regarding the regulation of Mcl-1, from transcription to degradation, focusing on aspects that have not yet been described in detail.
The most common type of lung cancer is adenocarcinoma (ADC), comprising around 40% of all lung cancer cases. In spite of achievements in understanding the pathogenesis of this disease and the ...development of new approaches in its treatment, unfortunately, lung ADC is still one of the most aggressive and rapidly fatal tumor types with overall survival less than 5 years. Lung ADC is often diagnosed at advanced stages involving disseminated metastatic tumors. This is particularly important for the successful development of new approaches in cancer therapy. The high resistance of lung ADC to conventional radiotherapies and chemotherapies represents a major challenge for treatment effectiveness. Here we discuss recent advances in understanding the molecular pathways driving tumor progression and related targeted therapies in lung ADCs. In addition, the cell death mechanisms induced by different treatment strategies and their contribution to therapy resistance are analyzed. The focus is on approaches to overcoming drug resistance in order to improve future treatment decisions.
In addition to the established role of the mitochondria in energy metabolism, regulation of cell death has emerged as a second major function of these organelles. This seems to be intimately linked ...to their generation of reactive oxygen species (ROS), which have been implicated in mtDNA mutations, aging, and cell death. Mitochondrial regulation of apoptosis occurs by mechanisms, which have been conserved through evolution. Thus, many lethal agents target the mitochondria and cause release of cytochrome c and other pro-apoptotic proteins into the cytoplasm. Cytochrome c release is initiated by the dissociation of the hemoprotein from its binding to the inner mitochondrial membrane. Oxidation of cardiolipin reduces cytochrome c binding and increases the level of soluble cytochrome c in the intermembrane space. Subsequent release of the hemoprotein occurs by pore formation mediated by pro-apoptotic Bcl-2 family proteins, or by Ca(2+) and ROS-triggered mitochondrial permeability transition, although the latter pathway might be more closely associated with necrosis. Taken together, these findings have placed the mitochondria in the focus of current cell death research.
The past decade has revealed a new role for the mitochondria in cell metabolism – regulation of cell death pathways. Considering that most tumor cells are resistant to apoptosis, one might question ...whether such resistance is related to the particular properties of mitochondria in cancer cells that are distinct from those of mitochondria in non-malignant cells. This scenario was originally suggested by Otto Warburg, who put forward the hypothesis that a decrease in mitochondrial energy metabolism might lead to development of cancer. This review is devoted to the analysis of mitochondrial function in cancer cells, including the mechanisms underlying the upregulation of glycolysis, and how intervention with cellular bioenergetic pathways might make tumor cells more susceptible to anticancer treatment and induction of apoptosis.
Apoptosis might proceed through the activation of both caspase-dependent and -independent pathways. Apoptosis-inducing factor (AIF) was discovered as the first protein that mediated ...caspase-independent cell death. Initially, it was regarded as a soluble protein residing in the intermembrane space of mitochondria, from where it could be exported to the nucleus to participate in large-scale DNA fragmentation and chromatin condensation. However, later it was demonstrated that AIF is N-terminally anchored to the inner mitochondrial membrane. Hence, AIF must be liberated from its membrane anchor prior to being released into the cytosol. The current knowledge about the molecular mechanisms regulating the processing and release of AIF from the mitochondria will be summarized and discussed in this review.
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