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.

Reactive oxygen species, cellular redox systems and apoptosis

In 2009, the Nomenclature Committee on Cell Death (NCCD) proposed a set of recommendations for the definition of distinct cell death morphologies and for the appropriate use of cell death-related terminology, including 'apoptosis', 'necrosis' and 'mitotic catastrophe'. In view of the substantial progress in the biochemical and genetic exploration of cell death, time has come to switch from morphological to molecular definitions of cell death modalities. Here we propose a functional classification of cell death subroutines that applies to both in vitro and in vivo settings and includes extrinsic apoptosis, caspase-dependent or -independent intrinsic apoptosis, regulated necrosis, autophagic cell death and mitotic catastrophe. Moreover, we discuss the utility of expressions indicating additional cell death modalities. On the basis of the new, revised NCCD classification, cell death subroutines are defined by a series of precise, measurable biochemical features.

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Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012

Autophagy is a mechanism by which cellular material is delivered to lysosomes for degradation, leading to the basal turnover of cell components and providing energy and macromolecular precursors. Autophagy has opposing, context-dependent roles in cancer, and interventions to both stimulate and inhibit autophagy have been proposed as cancer therapies. This has led to the therapeutic targeting of autophagy in cancer to be sometimes viewed as controversial. In this Review, we suggest a way forwards for the effective targeting of autophagy by understanding the context-dependent roles of autophagy and by capitalizing on modern approaches to clinical trial design.

/pdf/targeting-autophagy-in-cancer-2pjcn0h04a.pdf

Targeting autophagy in cancer

Macroautophagy/autophagy is a conserved transport pathway where targeted structures are sequestered by phagophores, which mature into autophagosomes, and then delivered into lysosomes for degradati...

/pdf/chloroquine-inhibits-autophagic-flux-by-decreasing-29tresuftu.pdf

Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion.

Corrigendum to "Reactive oxygen species generated in different compartments induce cell death, survival, or senescence". [Free Radic. Biol. Med. 2013 Apr; 57:176-187.].

Vol. 210 No. 5, August 31, 2015. Pages [705–716][1].

It recently came to the authors’ attention that the tubulin loading control panels shown in [Figs. 2 G][2] and [S2][3] F were incorrect as a result of errors introduced during figure preparation. The authors apologize for these mistakes. The

/pdf/correction-degradation-of-hk2-by-chaperone-mediated-cuv4rksjg3.pdf

Correction: Degradation of HK2 by chaperone-mediated autophagy promotes metabolic catastrophe and cell death

In addition to the role of the mitochondria in energy metabolism, these organelles play a key role in cell death signaling. In particular, mitochondrial alterations, such as stimulation of reactive oxygen species (ROS) formation, decreased ATP synthesis, loss of membrane potential and the release of pro-apoptotic proteins from the mitochondrial intermembrane space (IMS), have been shown to be involved in, and often responsible for, various manifestations of cell death. Among the pro-apoptotic proteins to be released are cytochrome c and Apoptosis-Inducing Factor (AIF). While cytochrome c initiates caspase-dependent cell death, AIF leads to caspase-independent cell death. The release of pro-apoptotic proteins from the IMS is considered as a “point of no return” in apoptotic signaling, although the mechanisms regulating permeabilization of the outer mitochondrial membrane remain controversial. Two main mechanisms have been elaborated including the induction of mitochondrial permeability transition (MPT) and selective pore formation by the Bcl-2 (B-cell lymphoma 2) family proteins, Bax and Bak. Although, distinct cell death pathways can be triggered by various signals, they often merge at a common regulator of this multistep process. Currently, it is widely accepted that the mitochondria serve as such a regulator. Therefore, the main goal of this project was to investigate the involvement of mitochondria in cell death. While cytosolic Bax is known to target the mitochondria to induce mitochondrial outer membrane permeabilization (MOMP) during apoptosis, less is known about its mitochondria-specific target. We addressed this issue and could show that a functional translocase of the outer mitochondrial membrane (TOM complex) is required for Bax to release cytochrome c from the mitochondria. Previous work in our group has established that AIF-mediated, and caspaseindependent apoptosis is the main cell death mechanism in non-small cell lung carcinomas treated with anticancer drugs. However, the molecular mechanisms underlying AIF release remained obscure. We addressed this issue and could show that Ca 2+ was imported into cells upon treatment of cells with protein kinase C (PKC) inhibitors. The imported Ca 2+ had two critical functions; a) the activation of a mitochondrial calpain that could cleave AIF, a step essential for its release and b) to stimulate mitochondrial ROS production. This, in turn, led to a selective posttranslational modification, carbonylation of AIF, which significantly sensitized AIF to calpain-mediated processing. Recently, we were also able to define the pathway by which Ca 2+ entered cells exposed to the PKC inhibitors. We found that the hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2) mediated a sustained Ca 2+ import, which was triggered by dephosphorylation of a critical residue within the conserved C-terminus of the channel in cells treated with PKC-inhibitors. Our findings reveal a novel role for the HCN2 channel in cell death signaling and uncover a new potential therapeutic drug target. List of Publications I. Ott M, Norberg E, Walter KM, Schreiner P, Kemper C, Rapaport D, Zhivotovsky B, Orrenius S. The mitochondrial TOM complex is required for tBid/Baxinduced cytochrome c release. J Biol Chem. 2007; 282,27633-27639. II. Norberg E, Gogvadze V, Ott M, Horn M, Uhlen P, Orrenius S, Zhivotovsky B. An increase in intracellular Ca2+ is required for the activation of mitochondrial calpain to release AIF during cell

/pdf/mitochondrial-involvement-in-cell-death-release-of-pro-26tifa82i5.pdf

Erik Norberg

Papers

Corrigendum to "Reactive oxygen species generated in different compartments induce cell death, survival, or senescence". [Free Radic. Biol. Med. 2013 Apr; 57:176-187.].

Correction: Degradation of HK2 by chaperone-mediated autophagy promotes metabolic catastrophe and cell death

Mitochondrial involvement in cell death: release of pro-apoptotic proteins

S04-4Mitochondrial involvement in cell death

Extraction of Metabolites from Cancer Cells.