BBA - Molecular Cell Research (v.1813, #4)
Editorial Board (i).
Preface to Mitochondria: The deadly organelle by G. Häcker; C. Borner (507).
BH3-only proteins: Orchestrators of apoptosis by Aisha Shamas-Din; Hetal Brahmbhatt; Brian Leber; David W. Andrews (508-520).
The BH3-only proteins of Bcl-2 family are essential initiators of apoptosis that propagate extrinsic and intrinsic cell death signals. The interaction of BH3-only proteins with other Bcl-2 family members is critical for understanding the core machinery that controls commitment to apoptosis by permeabilizing the mitochondrial outer membrane. BH3-only proteins promote apoptosis by both directly activating Bax and Bak and by suppressing the anti-apoptotic proteins at the mitochondria and the endoplasmic reticulum. To prevent constitutive cell death, BH3-only proteins are regulated by a variety of mechanisms including transcription and post-translational modifications that govern specific protein–protein interactions. Furthermore, BH3-only proteins also control the initiation of autophagy, another important pathway regulating cell survival and death. Emerging evidence indicates that the interaction of BH3-only proteins with membranes regulates binding to other Bcl-2 family members, thereby specifying function. Due to the important role of BH3-only proteins in the regulation of cell death, several promising BH3-mimetic drugs that are active in pre-clinical models are currently being tested as anti-cancer agents. This article is part of a Special Issue entitled Mitochondria: the deadly organelle.► The diversity in the structures of BH3-only proteins reflects a range of functions. ► The mechanism(s) and importance of BH3-only proteins binding to membranes. ► BH3-only proteins activate and inhibit multi-region Bcl-2 family proteins. ► BH3-only proteins at the endoplasmic reticulum function in apoptosis and autophagy. ► BH3-mimetics are potential drugs for cancer therapy.
Keywords: Apoptosis; Bcl-2 family protein; BH3-only protein; Conformational change; Autophagy; BH3 mimetic;
Molecular biology of Bax and Bak activation and action by Dana Westphal; Grant Dewson; Peter E. Czabotar; Ruth M. Kluck (521-531).
Bax and Bak are two nuclear-encoded proteins present in higher eukaryotes that are able to pierce the mitochondrial outer membrane to mediate cell death by apoptosis. Thus, organelles recruited by nucleated cells to supply energy can be recruited by Bax and Bak to kill cells. The two proteins lie in wait in healthy cells where they adopt a globular α-helical structure, seemingly as monomers. Following a variety of stress signals, they convert into pore-forming proteins by changing conformation and assembling into oligomeric complexes in the mitochondrial outer membrane. Proteins from the mitochondrial intermembrane space then empty into the cytosol to activate proteases that dismantle the cell. The arrangement of Bax and Bak in membrane-bound complexes, and how the complexes porate the membrane, is far from being understood. However, recent data indicate that they first form symmetric BH3:groove dimers which can be linked via an interface between the α6-helices to form high order oligomers. Here, we review how Bax and Bak change conformation and oligomerize, as well as how oligomers might form a pore. This article is part of a Special Issue entitled Mitochondria: the deadly organelle.► During apoptosis, Bax and Bak puncture the mitochondrial outer membrane. ► Bax and Bak activity is regulated by other members of the Bcl-2 family. ► Activation exposes the Bax and Bak BH3 domains to allow oligomerization. ► Bax and Bak oligomers form pores in the outer membrane via unknown mechanisms. ► Structures of oligomeric Bax or Bak may reveal novel drug targets.
Keywords: Apoptosis; Bak; Bax; Conformation change; Mitochondrion; Mitochondrial permeability; Oligomerization;
Bcl-2 proteins and mitochondria—Specificity in membrane targeting for death by Jennefer Lindsay; Mauro Degli Esposti; Andrew P. Gilmore (532-539).
The localization and control of Bcl-2 proteins on mitochondria is essential for the intrinsic pathway of apoptosis. Anti-apoptotic Bcl-2 proteins reside on the outer mitochondrial membrane (OMM) and prevent apoptosis by inhibiting the activation of the pro-apoptotic family members Bax and Bak. The Bcl-2 subfamily of BH3-only proteins can either inhibit the anti-apoptotic proteins or directly activate Bax or Bak. How these proteins interact with each other, the mitochondrial surface and within the OMM are complex processes we are only beginning to understand. However, these interactions are fundamental for the transduction of apoptotic signals to mitochondria and the subsequent release of caspase activating factors into the cytosol. In this review we will discuss our knowledge of how Bcl-2 proteins are directed to mitochondria in the first place, a crucial but poorly understood aspect of their regulation. This article is part of a Special Issue entitled Mitochondria: the deadly organelle.► This review highlights the various mechanisms that target Bcl-2 proteins to mitochondria. ► Multi-domain Bcl-2 proteins target to mitochondria via their C-terminal tail anchor. ► How membrane specificity is achieved for tail anchor containing Bcl-2 proteins is unclear, and may require interactions with other mitochondrial proteins. ► The mechanisms targeting BH3-only proteins to mitochondria are distinct from those used by the multi-domain proteins. ► Targeting of BH3 proteins involves both protein-lipid and protein-protein interactions on the OMM.
Keywords: Bcl-2; Mitochondria; Apoptosis; Bax; Bid; MOMP; Membrane lipids; Tail-anchor sequence;
Mitochondrial outer membrane permeabilization during apoptosis: The role of mitochondrial fission by Thomas Landes; Jean-Claude Martinou (540-545).
Mitochondria continually fuse and divide to yield a dynamic interconnected network throughout the cell. During apoptosis, concomitantly with permeabilization of the mitochondrial outer membrane (MOMP) and cytochrome c release, mitochondria undergo massive fission. This results in the formation of small, round organelles that tend to aggregate around the nucleus. Under some circumstances, preceding their fission, mitochondria tend to elongate and to hyperfuse, a process that is interpreted as a cell defense mechanism. Since many years, there is a controversy surrounding the physiological relevance of mitochondrial fragmentation in apoptosis. In this review, we present recent advances in this field, describe the mechanisms that underlie this process, and discuss how they could cooperate with Bax to trigger MOMP and cytochrome c release. This article is part of a Special Issue entitled Mitochondria: the deadly organelle.► Mitochondria continually fuse and divide. ► As a result, they form a dynamic network of interconnected organelles. ► Collapse of this network is observed early during apoptosis. ► We address the mechanisms underlying the mitochondrial fragmentation. ► We review how it contributes to cell death.
Keywords: Mitochondria; Apoptosis; Fission; Fusion; Bax; Drp1;
Apoptogenic factors released from mitochondria by David L. Vaux (546-550).
When cells kill themselves, they usually do so by activating mechanisms that have evolved specifically for that purpose. These mechanisms, which are broadly conserved throughout the metazoa, involve two processes: activation in the cytosol of latent cysteine proteases (termed caspases), and disruption of mitochondrial functions. These processes are linked in a number of different ways. While active caspases can cleave proteins in the mitochondrial outer membrane, and cleave and thereby activate certain pro-apoptotic members of the Bcl-2 family, proteins released from the mitochondria can trigger caspase activation and antagonise IAP family proteins. This review will focus on the pro-apoptotic molecules that are released from the mitochondria of cells endeavouring to kill themselves. This article is part of a Special Issue entitled Mitochondria: the deadly organelle.► Proteins are released from mitochondria during apoptosis. ► Several of these proteins can bind to IAPs, but they do not appear to be important regulators of cell death. ► During apoptosis, cytochrome c released from mitochondria is essential for activation of Apaf-1, which in turn activates caspases. ► AIF and endoG are released from mitochondria during apoptosis, but this is neither sufficient nor required for cell death.
Keywords: Apoptosis; Mitochondria; Release; Membrane; Permeability; Cytochrome c;
Apoptosis-induced changes in mitochondrial lipids by Massimo Crimi; Mauro Degli Esposti (551-557).
Apoptosis is an active and tightly regulated form of cell death, which can also be considered a stress-induced process of cellular communication. Recent studies reveal that the lipid network within cells is involved in the regulation and propagation of death signalling. Despite the vast growth of our current knowledge on apoptosis, little is known of the specific role played by lipid molecules in the central event of apoptosis—the piercing of mitochondrial membranes. Here we review the information regarding changes in mitochondrial lipids that are associated with apoptosis and discuss whether they may be involved in the permeabilization of mitochondria to release their apoptogenic factors, or just lie downstream of this permeabilization leading to the amplification of caspase activation. We focus on the earliest changes that physiological apoptosis induces in mitochondrial membranes, which may derive from an upstream alteration of phospholipid metabolism that reverberates on the mitochondrial re-modelling of their characteristic lipid, cardiolipin. Hopefully, this review will lead to an increased understanding of the role of mitochondrial lipids in apoptosis and also help revealing new stress sensing mechanisms in cells. This article is part of a Special Issue entitled Mitochondria: the deadly organelle.► After apoptosis induction, the initial lipid changes occurring in mitochondria appear to reflect an upstream deficiency in the biosynthesis of phospholipids including cardiolipin. ► Lysolipids are prominent among these initial changes and may facilitate the pro-apoptotic action of Bax and Bak that produces the piercing of mitochondria. ► Pro-apoptotic Bid provides a link between phospholipid deficiency and mitochondrial membranes by transporting lysolipids and binding to cardiolipin, affecting its re-modelling. ► Other changes in membrane lipids generally occur after the piercing of the outer mitochondrial membrane has occurred.
Keywords: Mitochondria; Cardiolipin; Lysophosphatidyl-choline; MOMP; Bid; Bcl-2; Death receptor; Apoptosis; Membrane lipids;
Caspase-8 and Bid: Caught in the act between death receptors and mitochondria by Chahrazade Kantari; Henning Walczak (558-563).
Mitochondria play a central role in maintaining cells alive, but are also important mediators of cell death. The main event in mitochondrial signalling and control of apoptosis is the permeabilisation of the outer mitochondrial membrane and the release of pro-apoptotic proteins into the cytosol from the mitochondrial intermembrane space. With respect to death receptor-mediated apoptosis, the activation of the mitochondrial pathway is required for apoptosis induction in cells which are described as “type II” cells whereas “type I” cells do not require it. In type I cells, activation of the extrinsic pathway is sufficient to induce apoptosis. This review deals with the events that enable cell death in type II cells, i.e., the signals that lead from death receptor stimulation to permeabilisation of the outer mitochondrial membrane. Caspase-8 and Bid are the known procurers of the death signal in this part of the apoptotic pathway. Currently many exciting new findings are emerging concerning the regulation of caspase-8 and Bid function and activation. We will take you on a journey through these new developments and point out what we consider the major unknowns in this field. We end our review on an up-to-date discussion of the determinants of the type I–type II cell distinction. This article is part of a Special Issue entitled Mitochondria: the deadly organelle.► We describe the role of mitochondria in caspase-8 signalling. ► Polyubiquitination of caspase-8 at the DISC modulates its activation. ► The cardiolipin enriched “mitosome” is a new activation platform for caspase-8. ► MTCH2/MIMP facilitates the recruitment of active tBid to the mitochondria. ► The type I/type II cell discrimination is also due to differences on XIAP levels.
Keywords: Caspase-8; Mitochondria; Bid; Type II cells; Death inducing signalling complex; XIAP;
Integrating stress signals at the endoplasmic reticulum: The BCL-2 protein family rheostat by Diego Rodriguez; Diego Rojas-Rivera; Claudio Hetz (564-574).
The assembling of distinct signaling protein complexes at the endoplasmic reticulum (ER) membrane controls several stress responses related to calcium homeostasis, autophagy, ER morphogenesis and protein folding. Diverse pathological conditions interfere with the function of the ER altering protein folding, a condition known as “ER stress”. Adaptation to ER stress depends on the activation of the unfolded protein response (UPR) and protein degradation pathways such as autophagy. Under chronic or irreversible ER stress, cells undergo apoptosis, where the BCL-2 protein family plays a crucial role at the mitochondria to trigger cytochrome c release and apoptosome assembly. Several BCL2 family members also regulate physiological processes at the ER through dynamic interactomes. Here we provide a comprehensive view of the roles of the BCL-2 family of proteins in mediating the molecular crosstalk between the ER and mitochondria to initiate apoptosis, in addition to their emerging functions in adaptation to stress, including autophagy, UPR, calcium homeostasis and organelle morphogenesis. We envision a model where BCL-2-containing complexes may operate as stress rheostats that, beyond their known apoptosis functions at the mitochondria, determine the amplitude and kinetics of adaptive responses against ER-related injuries. This article is part of a Special Issue entitled Mitochondria: the deadly organelle.▶ BCL-2 family of proteins control apoptosis at the mitochondria. ▶ Some BCL-2 family members regulate stress responses from the ER. ▶ Dynamic BCL-2 proteins-containing complexes regulate adaptation to stress. ▶ BCL-2 family members modulates IRE1α by forming part of the UPRosome.
Keywords: Endoplasmic reticulum; Unfolded protein response; BCL-2 family;
Mitochondrial localization of viral proteins as a means to subvert host defense by Céline Castanier; Damien Arnoult (575-583).
Viruses have developed a battery of distinct strategies to overcome the very sophisticated defense mechanisms of the infected host. Throughout the process of pathogen–host co-evolution, viruses have therefore acquired the capability to prevent host cell apoptosis because elimination of infected cells via apoptosis is one of the most ancestral defense mechanism against infection. Conversely, induction of apoptosis may favor viral dissemination as a result of the dismantlement of the infected cells. Mitochondria have been long recognized for their key role in the modulation of apoptosis but more recently, mitochondria have been shown to serve as a crucial platform for innate immune signaling as illustrated by the identification of MAVS. Thus, it is therefore not surprising that this organelle represents a recurrent target for viruses, aiming to manipulate the fate of the infected host cell or to inhibit innate immune response. In this review, we highlight the viral proteins that are specifically targeted to the mitochondria to subvert host defense. This article is part of a Special Issue entitled Mitochondria: the deadly organelle.►▸ Mitochondrion plays a pivotal role in apoptosis. ►▸Apoptosis of infected cells is a defense mechanism against viral infection. ►▸Induction of apoptosis may favor viral dissemination. ►▸Viruses express proteins that are targeted to mitoc
Keywords: Virus; Mitochondria; Apoptosis; Innate immunity;
Nuclear proteins acting on mitochondria by Liora Lindenboim; Christoph Borner; Reuven Stein (584-596).
An important mechanism in apoptotic regulation is changes in the subcellular distribution of pro- and anti-apoptotic proteins. Among the proteins that change in their localization and may promote apoptosis are nuclear proteins. Several of these nuclear proteins such as p53, Nur77, histone H1.2, and nucleophosmin were reported to accumulate in the cytosol and/or mitochondria and to promote the mitochondrial apoptotic pathway in response to apoptotic stressors. In this review, we will discuss the functions of these and other nuclear proteins in promoting the mitochondrial apoptotic pathway, the mechanisms that regulate their accumulation in the cytosol and/or mitochondria and the potential role of Bax and Bak in this process. This article is part of a Special Issue entitled Mitochondria: the deadly organelle.► Nuclear proteins translocate to the cytosol/mitochondria. ► The translocated nuclear proteins may act on the mitochondrial apoptotic gateway. ► Bax/Bak can regulate nuclear protein redistribution.
Keywords: Nuclear proteins; Protein translocation; Mitochondria; Bax; Bak;
Mitochondrial involvement in cell death of non-mammalian eukaryotes by Eltyeb Abdelwahid; Stephane Rolland; Xinchen Teng; Barbara Conradt; J. Marie Hardwick; Kristin White (597-607).
Although mitochondria are essential organelles for long-term survival of eukaryotic cells, recent discoveries in biochemistry and genetics have advanced our understanding of the requirements for mitochondria in cell death. Much of what we understand about cell death is based on the identification of conserved cell death genes in Drosophila melanogaster and Caenorhabditis elegans. However, the role of mitochondria in cell death in these models has been much less clear. Considering the active role that mitochondria play in apoptosis in mammalian cells, the mitochondrial contribution to cell death in non-mammalian systems has been an area of active investigation. In this article, we review the current research on this topic in three non-mammalian models, C. elegans, Drosophila, and Saccharomyces cerevisiae. In addition, we discuss how non-mammalian models have provided important insight into the mechanisms of human disease as they relate to the mitochondrial pathway of cell death. The unique perspective derived from each of these model systems provides a more complete understanding of mitochondria in programmed cell death. This article is part of a Special Issue entitled Mitochondria: the deadly organelle.► Mitochondrial role in cell death is actively studied in non-mammalian eukaryotes. ► Role of proapoptotic mitochondrial proteins is unclear. ► Mitochondrial fragmentation and altered morphogenesis are conserved. ► These are useful models to examine mitochondrial cell death pathways in human disease.
Keywords: Apoptosis; Mitochondria; C. elegans; Drosophila; Yeast;
Mathematical modelling of the mitochondrial apoptosis pathway by Heinrich J. Huber; Heiko Duessmann; Jakub Wenus; Seán M. Kilbride; Jochen H.M. Prehn (608-615).
Mitochondria are pivotal for cellular bioenergetics, but are also a core component of the cell death machinery. Hypothesis-driven research approaches have greatly advanced our understanding of the role of mitochondria in cell death and cell survival, but traditionally focus on a single gene or specific signalling pathway at a time. Predictions originating from these approaches become limited when signalling pathways show increased complexity and invariably include redundancies, feedback loops, anisotropies or compartmentalisation. By introducing methods from theoretical chemistry, control theory, and biophysics, computational models have provided new quantitative insights into cell decision processes and have led to an increased understanding of the key regulatory principles of apoptosis. In this review, we describe the currently applied modelling approaches, discuss the suitability of different modelling techniques, and evaluate their contribution to the understanding of the mitochondrial apoptosis pathway. This article is part of a Special Issue entitled Mitochondria: the deadly organelle.► Review of current mathematical modelling approaches in literature. ► Workflow for model development. ► Overview over current modelling techniques and their mathematical frameworks. ► Discussions of the benefits of modelling and outlook.
Keywords: Modelling; Systems biology; Mitochondria; Apoptosis;
Is mPTP the gatekeeper for necrosis, apoptosis, or both? by Kathleen W. Kinnally; Pablo M. Peixoto; Shin-Young Ryu; Laurent M. Dejean (616-622).
Permeabilization of the mitochondrial membranes is a crucial step in apoptosis and necrosis. This phenomenon allows the release of mitochondrial death factors, which trigger or facilitate different signaling cascades ultimately causing the execution of the cell. The mitochondrial permeability transition pore (mPTP) has long been known as one of the main regulators of mitochondria during cell death. mPTP opening can lead to matrix swelling, subsequent rupture of the outer membrane, and a nonspecific release of intermembrane space proteins into the cytosol. While mPTP was purportedly associated with early apoptosis, recent observations suggest that mitochondrial permeabilization mediated by mPTP is generally more closely linked to events of late apoptosis and necrosis. Mechanisms of mitochondrial membrane permeabilization during cell death, involving three different mitochondrial channels, have been postulated. These include the mPTP in the inner membrane, and the mitochondrial apoptosis-induced channel (MAC) and voltage-dependent anion-selective channel (VDAC) in the outer membrane. New developments on mPTP structure and function, and the involvement of mPTP, MAC, and VDAC in permeabilization of mitochondrial membranes during cell death are explored. This article is part of a Special Issue entitled Mitochondria: the deadly organelle.► Molecular identity of the mPTP: still a work in progress. ► MOMP is primarily associated with MAC opening during apoptosis. ► Sustained MPT is mostly involved during necrosis. ► A crosstalk between MAC and mPTP links both necrotic and apoptotic processes during cell death.
Keywords: mPTP, mitochondrial permeability transition pore; MAC, mitochondrial apoptosis-induced channel; VDAC, voltage-dependent anion-selective channel; Bcl-2 family proteins; Patch clamp; pharmacology;
Mitophagy and Parkinson's disease: The PINK1–parkin link by Emma Deas; Nicholas W. Wood; Hélène Plun-Favreau (623-633).
The study of rare, inherited mutations underlying familial forms of Parkinson's disease has provided insight into the molecular mechanisms of disease pathogenesis. Mutations in these genes have been functionally linked to several key molecular pathways implicated in other neurodegenerative disorders, including mitochondrial dysfunction, protein accumulation and the autophagic-lysosomal pathway. In particular, the mitochondrial kinase PINK1 and the cytosolic E3 ubiquitin ligase parkin act in a common pathway to regulate mitochondrial function. In this review we discuss the recent evidence suggesting that the PINK1/parkin pathway also plays a critical role in the autophagic removal of damaged mitochondria–mitophagy. This article is part of a Special Issue entitled Mitochondria: the deadly organelle.► Upon mitochondrial membrane depolarisation, full-length PINK1 accumulates at the outer mitochondrial membrane and NIX translocates to the mitochondria. ► NIX and full-length PINK1 recruit parkin to the mitochondria, which leads to parkin-dependent ubiquitination of VDAC. ► Ubiquitination of VDAC recruits p62 while NIX recruits GABARAP to the mitochondria. ► NIX binds to LC3, which additionally binds p62. ► The combined effects of PINK1, parkin, NIX, VDAC, GABARAP, p62 and LC3 cause depolarised mitochondria to be removed via mitochondrial autophagy – mitophagy.
Keywords: Mitochondria; Mitophagy; Neurodegeneration; Parkinson's disease; Parkin; PINK1;
Mitochondrial longevity pathways by M.H. Vendelbo; K.S. Nair (634-644).
Average lifespan has increased over the last centuries, as a consequence of medical and environmental factors, but maximal life span remains unchanged. Better understanding of the underlying mechanisms of aging and determinants of life span will help to reduce age-related morbidity and facilitate healthy aging. Extension of maximal life span is currently possible in animal models with measures such as genetic manipulations and caloric restriction (CR). CR appears to prolong life by reducing oxidative damage. Reactive oxygen species (ROS) have been proposed to cause deleterious effects on DNA, proteins, and lipids, and generation of these highly reactive molecules takes place in the mitochondria. But ROS is positively implicated in cellular stress defense mechanisms and formation of ROS a highly regulated process controlled by a complex network of intracellular signaling pathways. There are endogenous anti-oxidant defense systems that have the potential to partially counteract ROS impact. In this review, we will describe pathways contributing to the regulation of the age-related decline in mitochondrial function and their impact on longevity. This article is part of a Special Issue entitled Mitochondria: the deadly organelle.► Although average human life span increased maximal life span is static. ► Genetic manipulation and caloric restriction extend maximal lifespan. ► Reactive oxygen species (ROS) damages DNA proteins and lipids. ► Decline in mitochondrial DNA is a hallmark of aging but is partially reversed by exercise.
Keywords: Mitochondria; Longevity; Lifespan; ROS; Oxidative damage; Caloric restriction;
Cell metabolism: An essential link between cell growth and apoptosis by Emily F. Mason; Jeffrey C. Rathmell (645-654).
Growth factor-stimulated or cancerous cells require sufficient nutrients to meet the metabolic demands of cell growth and division. If nutrients are insufficient, metabolic checkpoints are triggered that lead to cell cycle arrest and the activation of the intrinsic apoptotic cascade through a process dependent on the Bcl-2 family of proteins. Given the connections between metabolism and apoptosis, the notion of targeting metabolism to induce cell death in cancer cells has recently garnered much attention. However, the signaling pathways by which metabolic stresses induce apoptosis have not as of yet been fully elucidated. Thus, the best approach to this promising therapeutic avenue remains unclear. This review will discuss the intricate links between metabolism, growth, and intrinsic apoptosis and will consider ways in which manipulation of metabolism might be exploited to promote apoptotic cell death in cancer cells. This article is part of a Special Issue entitled Mitochondria: the deadly organelle.►Growth stimuli and nutrient availability must be matched to avoid apoptotic stress. ►Oncogenic kinases can drive metabolism in growth factor deficiency. ►Bcl-2 family proteins respond to nutrient limitation to promote apoptosis. ►P53 plays a major role to mediate nutrient stress and induce Puma expression. ►Puma and Noxa promote while Mcl-1 suppresses apoptosis in nutrient deficiency.
Keywords: Apoptosis; Bcl-2; Metabolic checkpoint; p53; Akt;