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.

https://biblio.ugent.be/publication/8555786/file/8555788.pdf

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

Cells may die from accidental cell death (ACD) or regulated cell death (RCD). ACD is a biologically uncontrolled process, whereas RCD involves tightly structured signaling cascades and molecularly defined effector mechanisms. A growing number of novel non-apoptotic forms of RCD have been identified and are increasingly being implicated in various human pathologies. Here, we critically review the current state of the art regarding non-apoptotic types of RCD, including necroptosis, pyroptosis, ferroptosis, entotic cell death, netotic cell death, parthanatos, lysosome-dependent cell death, autophagy-dependent cell death, alkaliptosis and oxeiptosis. The in-depth comprehension of each of these lethal subroutines and their intercellular consequences may uncover novel therapeutic targets for the avoidance of pathogenic cell loss.

https://biblio.ugent.be/publication/8616364/file/8616366.pdf

The molecular machinery of regulated cell death

它是美国国立医学图书馆（NLM）生产的国际性生物医学文献联机书目数据库，是美国国立医学图书馆MEDLARS系统30多个数据库中最大的一个数据库，是世界上最著名的生物医学数据库之一。其内容相当于3种印刷本检索刊物：《医学索引》（index medicus，IM）、《牙科文献索引》、《国际护理学索引》，收录了1966年以来的70多个国家4300多种期刊的题录和文摘共1100万条记录，

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Neuronal cell death occurs extensively during development and pathology, where it is especially important because of the limited capacity of adult neurons to proliferate or be replaced. The concept of cell death used to be simple as there were just two or three types, so we just had to work out which type was involved in our particular pathology and then block it. However, we now know that there are at least a dozen ways for neurons to die, that blocking a particular mechanism of cell death may not prevent the cell from dying, and that non-neuronal cells also contribute to neuronal death. We review here the mechanisms of neuronal death by intrinsic and extrinsic apoptosis, oncosis, necroptosis, parthanatos, ferroptosis, sarmoptosis, autophagic cell death, autosis, autolysis, paraptosis, pyroptosis, phagoptosis, and mitochondrial permeability transition. We next explore the mechanisms of neuronal death during development, and those induced by axotomy, aberrant cell-cycle reentry, glutamate (excitoxicity and oxytosis), loss of connected neurons, aggregated proteins and the unfolded protein response, oxidants, inflammation, and microglia. We then reassess which forms of cell death occur in stroke and Alzheimer's disease, two of the most important pathologies involving neuronal cell death. We also discuss why it has been so difficult to pinpoint the type of neuronal death involved, if and why the mechanism of neuronal death matters, the molecular overlap and interplay between death subroutines, and the therapeutic implications of these multiple overlapping forms of neuronal death.

Neuronal Cell Death.

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.

Necroptosis in development, inflammation and disease

Mutations in the optineurin (OPTN) gene have been implicated in both familial and sporadic amyotrophic lateral sclerosis (ALS). However, the role of this protein in the central nervous system (CNS) and how it may contribute to ALS pathology are unclear. Here, we found that optineurin actively suppressed receptor-interacting kinase 1 (RIPK1)-dependent signaling by regulating its turnover. Loss of OPTN led to progressive dysmyelination and axonal degeneration through engagement of necroptotic machinery in the CNS, including RIPK1, RIPK3, and mixed lineage kinase domain-like protein (MLKL). Furthermore, RIPK1- and RIPK3-mediated axonal pathology was commonly observed in SOD1(G93A) transgenic mice and pathological samples from human ALS patients. Thus, RIPK1 and RIPK3 play a critical role in mediating progressive axonal degeneration. Furthermore, inhibiting RIPK1 kinase may provide an axonal protective strategy for the treatment of ALS and other human degenerative diseases characterized by axonal degeneration.

/pdf/ripk1-mediates-axonal-degeneration-by-promoting-inflammation-50qhs528b2.pdf

RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS.

Stimulation of TNFR1 by TNFα can promote three distinct alternative mechanisms of cell death: necroptosis, RIPK1-independent and -dependent apoptosis. How cells decide which way to die is unclear. Here, we report that TNFα-induced phosphorylation of RIPK1 in the intermediate domain by TAK1 plays a key role in regulating this critical decision. Using phospho-Ser321 as a marker, we show that the transient phosphorylation of RIPK1 intermediate domain induced by TNFα leads to RIPK1-independent apoptosis when NF-κB activation is inhibited by cycloheximide. On the other hand, blocking Ser321 phosphorylation promotes RIPK1 activation and its interaction with FADD to mediate RIPK1-dependent apoptosis (RDA). Finally, sustained phosphorylation of RIPK1 intermediate domain at multiple sites by TAK1 promotes its interaction with RIPK3 and necroptosis. Thus, absent, transient and sustained levels of TAK1-mediated RIPK1 phosphorylation may represent distinct states in TNF-RSC to dictate the activation of three alternative cell death mechanisms, RDA, RIPK1-independent apoptosis and necroptosis.

https://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=4245&context=oapubs

Regulation of RIPK1 activation by TAK1-mediated phosphorylation dictates apoptosis and necroptosis.

Drug combinations have been increasingly applied in chemotherapy as a strategy to enhance the efficacy of anti-cancer treatment. The appropriate drug combinations may achieve synergistic effects beyond monotherapies alone. AC220 (Quizartinib), an FLT3 receptor tyrosine kinase inhibitor, developed for the treatment of AML, has been tested in phase II human clinical trials. However, AC220 as a monotherapy is not efficacious enough. In this study, we performed a small-molecule screening of 12 640 compounds in order to find a compound that increase the AC220 efficacy in chemotherapy. We identified that TAK-165, a HER2 inhibitor, even when used at low nanomolar doses in combination with AC220, was able to induce cell death in different cancer cells, but not in non-cancer cell lines. We showed that TAK-165 and AC220 act synergistically to downregulate key signaling pathways and potently induce cancer cell death. Furthermore, we demonstrated that TAK-165 inhibited autophagy in a HER2-independent manner. Finally, we showed that the combination of TAK-165 and AC220 induced cell death in cancer cells through the activation of chaperone-mediated autophagy. Overall, these findings support the strategy for using AC220 and an autophagy inhibitor such as TAK-165 in a combinatorial treatment to enhance the efficacy of cancer therapies.

/pdf/synergistic-effect-of-a-novel-autophagy-inhibitor-and-1t239s6ckw.pdf

Synergistic effect of a novel autophagy inhibitor and Quizartinib enhances cancer cell death

Mitofusins reside on the outer mitochondrial membrane and regulate mitochondrial fusion, a physiological process that impacts diverse cellular processes. Mitofusins are activated by conformational changes and subsequently oligomerize to enable mitochondrial fusion. Here, we identify small molecules that directly increase or inhibit mitofusins activity by modulating mitofusin conformations and oligomerization. We use these small molecules to better understand the role of mitofusins activity in mitochondrial fusion, function, and signaling. We find that mitofusin activation increases, whereas mitofusin inhibition decreases mitochondrial fusion and functionality. Remarkably, mitofusin inhibition also induces minority mitochondrial outer membrane permeabilization followed by sub-lethal caspase-3/7 activation, which in turn induces DNA damage and upregulates DNA damage response genes. In this context, apoptotic death induced by a second mitochondria-derived activator of caspases (SMAC) mimetic is potentiated by mitofusin inhibition. These data provide mechanistic insights into the function and regulation of mitofusins as well as small molecules to pharmacologically target mitofusins. 

/pdf/modulating-mitofusins-to-control-mitochondrial-function-and-2soyoe8g.pdf

Amanda Tomie Ouchida

Papers

RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS.

Regulation of RIPK1 activation by TAK1-mediated phosphorylation dictates apoptosis and necroptosis.

Synergistic effect of a novel autophagy inhibitor and Quizartinib enhances cancer cell death

Modulating mitofusins to control mitochondrial function and signaling