Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018

Abstract

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

Fig. 1

Major cell death subroutines. Mammalian cells exposed to unrecoverable perturbations of the intracellular or extracellular microenvironment can activate one of many signal transduction cascades ultimately leading to their demise. Each of such regulated cell death (RCD) modes is initiated and propagated by molecular mechanisms that exhibit a considerable degree of interconnectivity. Moreover, each type of RCD can manifest with an entire spectrum of morphological features ranging from fully necrotic to fully apoptotic, and an immunomodulatory profile ranging from anti-inflammatory and tolerogenic to pro-inflammatory and immunogenic. ADCD: autophagy-dependent cell death, ICD: immunogenic cell death, LDCD: lysosome-dependent cell death, MPT: mitochondrial permeability transition.

Fig. 2

Interconnectivity of cell death from a therapeutic perspective. On the basis of the assumption that each regulated cell death (RCD) subroutine would operate in a virtually isolated manner (a), considerable efforts have been dedicated to the development of pharmacological agents that would interrupt RCD by operating on a single signal transduction module (b). It is now clear that the molecular mechanisms underlying distinct RCD modalities exhibit a considerable degree of interconnectivity (c). This implies that robust cytoprotection may not be achieved by targeting a single RCD subroutine, but only upon the simultaneous inhibition of multiple signal transduction modules (assuming that these modules are the actual cause of cell death, and not simple epiphenomena of RCD signaling (d).

Fig. 3

Causal vs. accessory aspects of cell death from a therapeutic perspective. Cells exposed to very harsh environmental conditions disassemble in a virtually instantaneous and uncontrollable manner, a process that is referred to as accidental cell death (ACD). Conversely, relatively mild perturbations of exogenous or endogenous origin promote adaptative stress responses aimed at the restoration of cellular homeostasis. If such responses fail, cells generally activate one or more of multiple, highly interconnected signal transduction modules that precipitate regulated cell death (RCD). ACD cannot be retarded by pharmacological or genetic interventions, and most (if not all) strategies conceived so far to block RCD in mammalian organisms fail to efficiently do so, at least in part owing to the elevated interconnectivity of the process. Conversely, some agents that de facto promote RCD by primarily targeting the underlying molecular machinery (rather than by targeting normal cellular functions) are already available for use in the clinic. The events that follow primary cell death—including a secondary wave of RCD in neighboring cells established (directly or indirectly) by molecules released from the cells succumbing to the primary insult, as well as danger-associated molecular pattern (DAMP) signaling—may also be targets for pharmacological interventions. Finally, although altering quantitatively the percentage of cells succumbing to primary RCD remains challenging (especially when a hitherto poorly defined point-of-no-return of the process has been trespassed), favoring the use of specific signaling modules over others may have prominent effects on long-term disease outcome.