Explore the vast range of titles available.

Death is the inevitable fate of all living organisms, whether at the individual or cellular level. For a long time, cell death was believed to be an undesirable but unavoidable final outcome of nonfunctioning cells, as inflammation was inevitably triggered in response to damage. However, experimental evidence accumulated over the past few decades has revealed different types of cell death that are genetically programmed to eliminate unnecessary or severely damaged cells that may damage surrounding tissues. Several types of cell death, including apoptosis, necrosis, autophagic cell death, and lysosomal cell death, which are classified as programmed cell death, and pyroptosis, necroptosis, and NETosis, which are classified as inflammatory cell death, have been described over the years. Recently, several novel forms of cell death, namely, mitoptosis, paraptosis, immunogenic cell death, entosis, methuosis, parthanatos, ferroptosis, autosis, alkaliptosis, oxeiptosis, cuproptosis, and erebosis, have been discovered and advanced our understanding of cell death and its complexity. In this review, we provide a historical overview of the discovery and characterization of different forms of cell death and highlight their diversity and complexity. We also briefly discuss the regulatory mechanisms underlying each type of cell death and the implications of cell death in various physiological and pathological contexts. This review provides a comprehensive understanding of different mechanisms of cell death that can be leveraged to develop novel therapeutic strategies for various diseases. Cell death mechanisms: implications for disease therapies Cell death is a complex and interconnected process that plays a crucial role in maintaining tissue homeostasis and preventing disease. There are various types of cell death, including necrosis, apoptosis, autophagy, and others, each with distinct morphological features and molecular mechanisms. Understanding the diverse processes underlying cell death is essential for understanding diseases and developing new therapies. Recent research has focused on characterizing and distinguishing various forms of cell death, thereby advancing our understanding of their roles in health and disease. The complex mechanisms underlying cell death are underscored by the intricate interconnections among different types of cell death and the regulation of these mechanisms through diverse signaling pathways and environmental factors. Further research is necessary to fully characterize and differentiate among the various forms of cell death and their roles in pathological conditions.

Regulated cell death mediated by dedicated molecular machines, known as programmed cell death, plays important roles in health and disease. Apoptosis, necroptosis and pyroptosis are three such programmed cell death modalities. The caspase family of cysteine proteases serve as key regulators of programmed cell death. During apoptosis, a cascade of caspase activation mediates signal transduction and cellular destruction, whereas pyroptosis occurs when activated caspases cleave gasdermins, which can then form pores in the plasma membrane. Necroptosis, a form of caspase-independent programmed necrosis mediated by RIPK3 and MLKL, is inhibited by caspase-8-mediated cleavage of RIPK1. Disruption of cellular homeostatic mechanisms that are essential for cell survival, such as normal ionic and redox balance and lysosomal flux, can also induce cell death without invoking programmed cell death mechanisms. Excitotoxicity, ferroptosis and lysosomal cell death are examples of such cell death modes. In this Review, we provide an overview of the major cell death mechanisms, highlighting the latest insights into their complex regulation and execution, and their relevance to human diseases.Cell death can result from the activation of dedicated programmed cell death machineries or disruption of pro-survival mechanisms. This Review describes the different major mechanisms of cell death and discusses recent insights into their relevance to disease.

Several years after the characterization of the role of receptor-interacting serine/threonine protein kinase 1 (RIPK1) in cell survival, inflammation and disease, RIPK1 was implicated in the regulation of a newly identified type of cell death known as necroptosis. This Timeline article describes the discoveries that shed light on the roles of RIPK1, RIPK3, mixed-lineage kinase domain-like protein (MLKL) and other regulators of necroptosis in controlling cell fate. In the early 2000s, receptor-interacting serine/threonine protein kinase 1 (RIPK1), a molecule already recognized as an important regulator of cell survival, inflammation and disease, was attributed an additional function: the regulation of a novel cell death pathway that came to be known as necroptosis. Subsequently, the related kinase RIPK3 and its substrate mixed-lineage kinase domain-like protein (MLKL) were also implicated in the necroptotic pathway, and links between this pathway and apoptosis were established. In this Timeline article, we outline the discoveries that have helped to identify the roles of RIPK1, RIPK3, MLKL and other regulators of necroptosis, and how they interact to determine cell fate.

Key Points During development, programmed cell death has various functions, including sculpting and deletion of structures, supply of nutrients, regulation of cell number and elimination of abnormal and dangerous cells. Several distinct mechanisms of programmed cell death are used to eliminate cells; we discuss the biological significance of these pathways in vivo . Caspase activation is subjected to many layers of coordinated upstream regulation, which ensure that the cell is killed only after several checkpoints have been cleared. Is autophagy a cell death mechanism? Here, we carefully review the data that support autophagy as a bona fide mechanism of cell destruction. For many years, necrosis was regarded as an unregulated mode of cell death that was caused by overwhelming trauma. Here, we examine a regulated form of necrosis termed necroptosis. Traditionally, it was thought that dying cells have limited effects on the cellular environment. However, it is now clear that apoptotic cells release signals that can trigger tissue regeneration. Cells that are undergoing apoptosis can instruct additional killing in their cellular environment, which explains how 'communal suicide' can occur. Apoptosis, autophagy and necroptosis are discussed in the context of molecular mechanisms of programmed cell death during development and tissue homeostasis. The signals that dying cells produce can in turn induce the apoptosis or proliferation of neighbouring cells. All life ends in death, but perhaps one of life's grander ironies is that it also depends on death. Cell-intrinsic suicide pathways, termed programmed cell death (PCD), are crucial for animal development, tissue homeostasis and pathogenesis. Originally, PCD was almost synonymous with apoptosis; recently, however, alternative mechanisms of PCD have been reported. Here, we provide an overview of several distinct PCD mechanisms, namely apoptosis, autophagy and necroptosis. In addition, we discuss the complex signals that emanate from dying cells, which can either trigger regeneration or instruct additional killing. Further advances in understanding the physiological roles of the various mechanisms of cell death and their associated signals will be important to selectively manipulate PCD for therapeutic purposes.

Through their many and varied metabolic functions, mitochondria power life. Paradoxically, mitochondria also have a central role in apoptotic cell death. Upon induction of mitochondrial apoptosis, mitochondrial outer membrane permeabilization (MOMP) usually commits a cell to die. Apoptotic signalling downstream of MOMP involves cytochrome c release from mitochondria and subsequent caspase activation. As such, targeting MOMP in order to manipulate cell death holds tremendous therapeutic potential across different diseases, including neurodegenerative diseases, autoimmune disorders and cancer. In this Review, we discuss new insights into how mitochondria regulate apoptotic cell death. Surprisingly, recent data demonstrate that besides eliciting caspase activation, MOMP engages various pro-inflammatory signalling functions. As we highlight, together with new findings demonstrating cell survival following MOMP, this pro-inflammatory role suggests that mitochondria-derived signalling downstream of pro-apoptotic cues may also have non-lethal functions. Finally, we discuss the importance and roles of mitochondria in other forms of regulated cell death, including necroptosis, ferroptosis and pyroptosis. Collectively, these new findings offer exciting, unexplored opportunities to target mitochondrial regulation of cell death for clinical benefit.Mitochondria are key executioners of apoptosis. However, it has recently become clear that beyond driving apoptosis, mitochondria also contribute to pro-inflammatory signalling and other types of regulated cell death. These functions are relevant to disease and could be targeted in the treatment of, for example, degenerative disorders, infection and cancer.

Key Points The constant deleterious modification of DNA by reactive molecules, endogenously or exogenously generated, is offset by protective processes that are initiated by the DNA damage response. The interplay of the diverse signalling cascades (DNA damage response) that originate from the interference of DNA lesions with replication and the transcriptome leads to the activation of DNA repair, autophagy, senescence, apoptosis and necroptosis. Aspects of how post-translational modifications of the tumour suppressor p53 determine the switch between these end points are discussed. The crosstalk between autophagy, senescence, apoptosis and regulated necrosis is also discussed, focusing on the importance of thresholds for deciding cell fate. Throughout this Review, emphasis is placed on how DNA damage and DNA repair fit within the complex cellular context. Understanding how DNA damage determines cell fate — DNA repair and cell survival or death — is important for gaining insight into carcinogenesis and in promoting successful cancer therapy. This Review describes key decision-making nodes in the complex interplay between DNA damage responses and cell fate signalling. DNA is vulnerable to damage resulting from endogenous metabolites, environmental and dietary carcinogens, some anti-inflammatory drugs, and genotoxic cancer therapeutics. Cells respond to DNA damage by activating complex signalling networks that decide cell fate, promoting not only DNA repair and survival but also cell death. The decision between cell survival and death following DNA damage rests on factors that are involved in DNA damage recognition, and DNA repair and damage tolerance, as well as on factors involved in the activation of apoptosis, necrosis, autophagy and senescence. The pathways that dictate cell fate are entwined and have key roles in cancer initiation and progression. Furthermore, they determine the outcome of cancer therapy with genotoxic drugs. Understanding the molecular basis of these pathways is important not only for gaining insight into carcinogenesis, but also in promoting successful cancer therapy. In this Review, we describe key decision-making nodes in the complex interplay between cell survival and death following DNA damage.

Autophagy influences cell survival through maintenance of cell bioenergetics and clearance of protein aggregates and damaged organelles. Several lines of evidence indicate that autophagy is a multifaceted regulator of cell death, but controversy exists over whether autophagy alone can drive cell death under physiologically relevant circumstances. Here, we review the role of autophagy in cell death and examine how autophagy interfaces with other forms of cell death including apoptosis and necrosis. In this Review, Doherty and Baehrecke discuss the multiple roles of autophagy during cell survival and cell death. They cover the interplay between autophagy, apoptosis and necrosis, as well as engulfment and inflammation.

In a majority of pathophysiological settings, cell death is not accidental — it is controlled by a complex molecular apparatus. Such a system operates like a computer: it receives several inputs that inform on the current state of the cell and the extracellular microenvironment, integrates them and generates an output. Thus, depending on a network of signals generated at specific subcellular sites, cells can respond to stress by attemptinwg to recover homeostasis or by activating molecular cascades that lead to cell death by apoptosis or necrosis. Here, we discuss the mechanisms whereby cellular compartments — including the nucleus, mitochondria, plasma membrane, endoplasmic reticulum, Golgi apparatus, lysosomes, cytoskeleton and cytosol — sense homeostatic perturbations and translate them into a cell-death-initiating signal.

Ferroptosis, a programmed cell death, has been identified and associated with cancer and various other diseases. Ferroptosis is defined as a reactive oxygen species (ROS)-dependent cell death related to iron accumulation and lipid peroxidation, which is different from apoptosis, necrosis, autophagy, and other forms of cell death. However, accumulating evidence has revealed a link between autophagy and ferroptosis at the molecular level and has suggested that autophagy is involved in regulating the accumulation of iron-dependent lipid peroxidation and ROS during ferroptosis. Understanding the roles and pathophysiological processes of autophagy during ferroptosis may provide effective strategies for the treatment of ferroptosis-related diseases. In this review, we summarize the current knowledge regarding the regulatory mechanisms underlying ferroptosis, including iron and lipid metabolism, and its association with the autophagy pathway. In addition, we discuss the contribution of autophagy to ferroptosis and elucidate the role of autophagy as a ferroptosis enhancer during ROS-dependent ferroptosis.