Essential versus accessory aspects of cell death: recommendations of the NCCD 2015

Abstract

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as 'accidental cell death' (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. 'Regulated cell death' (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death.

Figure 1

Types of cell death. Cells exposed to extreme physical, chemical or mechanical stimuli succumb in a completely uncontrollable manner, reflecting the immediate loss of structural integrity. We refer to such instances of cellular demise with the term ‘accidental cell death' (ACD). Alternatively, cell death can be initiated by a genetically encoded machinery. The course of such ‘regulated cell death' (RCD) variants can be influenced, at least to some extent, by specific pharmacologic or genetic interventions. The term ‘programmed cell death' (PCD) is used to indicate RCD instances that occur as part of a developmental program or to preserve physiologic adult tissue homeostasis

Figure 2

Regulated cell death and adaptive stress responses. Regulated cell death (RCD) is often initiated in the context of unsuccessful responses to perturbations of intracellular or extracellular homeostasis. Two mutually exclusive models can be put forward to explain how failing responses to stress initiate RCD (which in many instances constitutes a means to preserve the homeostasis of the whole organism or colony). First, according to a ‘conversion model', RCD-inhibitory signals simply cease at some stage of the adaptive response and are substituted by RCD-promoting ones. Second, a ‘competition model' postulates that RCD-inhibitory and -promoting signals coexist and counteract each other starting from the very detection of microenvironmental alterations, and at some stage the latter predominate over the former. Circumstantial evidence favors the ‘competition model' in a majority of experimental scenarios

Figure 3

Initiation, execution and propagation of regulated cell death. The term ‘execution' has largely been used to indicate the processes that (were thought to) mediate regulated cell death (RCD), such as the massive activation of CASP3 in the course of apoptosis. Conversely, the word ‘initiation' has generally been used to refer to the signal transduction events that trigger executioner mechanisms, such as the activation of CASP8 or CASP9, both of which normally impinge on CASP3. Upon an attentive re-evaluation of the available literature, the NCCD recommends caution in attributing a specific process a bona fide causative value in the execution of cell death. In addition, the NCCD proposes to use the term ‘initiation' with a pragmatic connotation, that is, to indicate the steps in the cascades of events leading to RCD that are truly reversible, and the term ‘propagation' to indicate the processes that link primary RCD to the insult-independent initiation of a secondary wave of RCD, that is, the release of cytotoxic and proinflammatory factors, including damage-associated molecular patterns (DAMPs), by dying cells and their consequences. Based on this conceptual construction, only pharmacologic and genetic interventions that target the initiation phase exert bona fide cytoprotective effects, that is, truly inhibit primary RCD rather than just delaying its course or changing its morphologic or biochemical correlates. Robust cytoprotection can also be achieved in vivo by the administration of anti-inflammatory agents and by measures that block DAMPs or their receptors. These maneuvers, however, appear to be efficient as they prevent the propagation of primary RCD or the initiation of secondary RCD

Figure 4

Declining ATP levels and redox alterations as a potential cause of regulated cell death. A growing amount of evidence indicates that the pharmacologic or genetic inhibition of the mechanisms that are commonly regarded as the executioners of regulated cell death (RCD) changes the kinetics of the process while altering its morphologic and biochemical manifestations, but fails to mediate bona fide long-term cytoprotection. It is therefore difficult to evaluate the actual causes that push cells beyond the point-of-no-return between life and death, especially as it remains to be formally demonstrated where the frontier between reversible alterations of homeostasis and the irreversible degeneration of cellular functions stands. ATP is required for a wide panel of vital activities, including the maintenance of the ionic equilibrium across the plasma membrane, implying that the drop of ATP concentrations below a specific threshold level may irremediably compromise the ability of cells to maintain structural integrity (which is the most reliable marker of cell death currently available). Along similar lines, variations in the oxidative potential of the intracellular milieu not only inhibit several enzymatic activities, including mitochondrial ATP synthesis, but also cause direct structural damage to organelles and membranes. We therefore hypothesize that declining ATP levels and a compromised redox homeostasis may constitute common causes of cell death in many RCD models. ROS, reactive oxygen species