Cell death in health and disease

Cell death is clearly an important factor in development, homeostasis, pathology and in aging, but medical efforts based on controlling cell death have not become major aspects of medicine. There are several reasons why hopes have been slow to be fulfilled, and they present indications for new directions in research. Most effort has focused on the machinery of cell death, or the proximate effectors of apoptosis and their closely associated and interacting proteins. But cells have many options other than apoptosis. These include autophagy, necrosis, atrophy and stepwise or other alternate means of self-disassembly. The response of a cell to a noxious or otherwise intimidating signal will depend heavily on the history, lineage and current status of the cell. Many metabolic and other processes adjust the sensitivity of cells to signals, and viruses aggressively attempt to regulate the death of their host cells. Another complicating factor is that many deathassociated proteins may have functions totally unrelated to their role in cell death, generating the possibility of undesirable side effects if one interferes with them. In the future, the challenge will be more to understand the challenge to the cell from a more global standpoint, including many more aspects of metabolism, and work toward alleviating or provoking the challenge in a targeted fashion

Activation of Cyclin-Dependent Kinase 5 Is a Consequence of Cell Death

Cyclin-dependent kinase 5 (Cdk5) is similar to other Cdks but is activated during cell differentiation and cell death rather than cell division. Since activation of Cdk5 has been reported in many situations leading to cell death, we attempted to determine if it was required for any form of cell death. We found that Cdk5 is activated during apoptotic deaths and that the activation can be detected even when the cells continue to secondary necrosis. This activation can occur in the absence of Bim, calpain, or neutral cathepsins. The kinase is typically activated by p25, derived from p35 by calpain-mediated cleavage, but inhibition of calpain does not affect cell death or the activation of Cdk5. Likewise, RNAi-forced suppression of the synthesis of Cdk5 does not affect the incidence or kinetics of cell death. We conclude that Cdk5 is activated as a consequence of metabolic changes that are common to many forms of cell death. Thus its activation suggests processes during cell death that will be interesting or important to understand, but activation of Cdk5 is not necessary for cells to die

The variability of autophagy and cell death susceptibility

Impaired autophagic machinery is implicated in a number of diseases such as heart disease, neurodegeneration and cancer. A common denominator in these pathologies is a dysregulation of autophagy that has been linked to a change in susceptibility to cell death. Although we have progressed in understanding the molecular machinery and regulation of the autophagic pathway, many unanswered questions remain. How does the metabolic contribution of autophagy connect with the cell’s history and how does its current autophagic flux affect metabolic status and susceptibility to undergo cell death? How does autophagic flux operate to switch metabolic direction and what are the underlying mechanisms in metabolite and energetic sensing, metabolite substrate provision and metabolic integration during the cellular stress response? In this article we focus on unresolved questions that address issues around the role of autophagy in sensing the energetic environment and its role in actively generating metabolite substrates. We attempt to provide answers by explaining how and when a change in autophagic pathway activity such as primary stress response is able to affect cell viability and when not. By addressing the dynamic metabolic relationship between autophagy, apoptosis and necrosis we provide a new perspective on the parameters that connect autophagic activity, severity of injury and cellular history in a logical manner. Last, by evaluating the cell’s condition and autophagic activity in a clear context of regulatory parameters in the intra- and extracellular environment, this review provides new concepts that set autophagy into an energetic feedback loop, that may assist in our understanding of autophagy in maintaining healthy cells or when it controls the threshold between cell death and cell survival

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

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

La mort cellulaire programmée: histoire et avenir d'un concept

La mort cellulaire est connue et comprise depuis le 19ème siècle, mais les études expérimentales n'ont commencé qu'au milieu du 20ème siècle. Vers les années 1960, plusieurs laboratoires montraient que la mort cellulaire est programmée de façon biologique et que les manifestations en sont communes à plusieurs types de mort cellulaire mais n'ont pas d'explication évidente, en particulier dans le cas de l'apoptose. En 1990 on connaissait l'origine génétique de la mort programmée et les premiers composants de la machinerie de la mort cellulaire (caspase 3, bcl-2 et Fas) étaient identifiés, séquencés, et reconnus comme hautement conservés. Le développement rapide de la recherche dans ce domaine nous a livré une bonne compréhension de la façon dont la mort cellulaire s'accomplit. Néanmoins, afin d'exploiter cette compréhension dans des buts thérapeutiques, il nous faut encore beaucoup apprendre sur la manière dont une cellule s'engage sur la voie de la mort. Nous devons également reconnaître que l'apoptose est peut-être le mode le plus habituel et le plus efficace de mort cellulaire, mais qu'il y a des voies alternatives, qui peuvent se terminer par la mort cellulaire même quand la voie apoptotique est bloquée. Il est intéressant de noter que la plupart des arguments et erreurs sur ce sujet ont été anticipés par Claude Bernard, dont les mises en garde et les recommandations restent valables à ce jour

The Joy of Science: An Examination of How Scientists Ask and Answer Questions Using the Story of Evolution as a Paradigm

The structure of this book is therefore tripartite. On the first level, we wish to demonstrate that, far from being arcane or inaccessible, the scientific approach is simply a variant of normal, common experience and judgment, easily accessible to any educated person. The second goal is to explain the structure of scientific thinking, which we will describe as the requirement for evidence, logic, and falsification (experimental testing). The third goal is to illustrate the scientific method by looking at the story of the development of the idea of evolution. Evolution is a branch of scientific inquiry that is distinguished by its minimal level of laboratory experimentation, as least in its early period. Nevertheless, the story of evolution seems for several reasons to be an excellent choice to examine the nature of scientific inquiry. First, it is, almost without doubt, the most important idea of the 19th and 20th centuries. Second, it is often misunderstood. Third, understanding the story does not require an extensive technical background