Alternative Cell Death Pathways and Cell Metabolism

While necroptosis has for long been viewed as an accidental mode of cell death triggered by physical or chemical damage, it has become clear over the last years that necroptosis can also represent a programmed form of cell death in mammalian cells. Key discoveries in the field of cell death research, including the identification of critical components of the necroptotic machinery, led to a revised concept of cell death signaling programs. Several regulatory check and balances are in place in order to ensure that necroptosis is tightly controlled according to environmental cues and cellular needs. This network of regulatory mechanisms includes metabolic pathways, especially those linked to mitochondrial signaling events. A better understanding of these signal transduction mechanisms will likely contribute to open new avenues to exploit our knowledge on the regulation of necroptosis signaling for therapeutic application in the treatment of human diseases.

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How treatments with endocrine and metabolic drugs influence pituitary cell function

Endocrine Connections ◽

10.1530/ec-19-0482 ◽

2020 ◽

Vol 9 (2) ◽

pp. R14-R27 ◽

Cited By ~ 2

Author(s):

Giovanni Tulipano

Keyword(s):

Protein Kinase ◽

Mammalian Cells ◽

Cell Function ◽

Cell Metabolism ◽

Cell Signalling ◽

Pituitary Cell ◽

Pituitary Cells ◽

Transduction Mechanisms ◽

Amp Activated Protein Kinase

A variety of endocrine and metabolic signals regulate pituitary cell function acting through the hypothalamus-pituitary neuroendocrine axes or directly at the pituitary level. The underlying intracellular transduction mechanisms in pituitary cells are still debated. AMP-activated protein kinase (AMPK) functions as a cellular sensor of low energy stores in all mammalian cells and promotes adaptive changes in response to calorie restriction. It is also regarded as a target for therapy of proliferative disorders. Various hormones and drugs can promote tissue-specific activation or inhibition of AMPK by enhancing or inhibiting AMPK phosphorylation, respectively. This review explores the preclinical studies published in the last decade that investigate the role of AMP-activated protein kinase in the intracellular transduction pathways downstream of endocrine and metabolic signals or drugs affecting pituitary cell function, and its role as a target for drug therapy of pituitary proliferative disorders. The effects of the hypoglycemic agent metformin, which is an indirect AMPK activator, are discussed. The multiple effects of metformin on cell metabolism and cell signalling and ultimately on cell function may be either dependent or independent of AMPK. The in vitro effects of metformin may also help highlighting differences in metabolic requirements between pituitary adenomatous cells and normal cells.

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Mitochondrial morphology and distribution in mammalian cells

Biological Chemistry ◽

10.1515/bc.2006.193 ◽

2006 ◽

Vol 387 (12) ◽

pp. 1551-1558 ◽

Cited By ~ 80

Author(s):

Ann E. Frazier ◽

Clement Kiu ◽

Diana Stojanovski ◽

Nicholas J. Hoogenraad ◽

Michael T. Ryan

Keyword(s):

Cell Death ◽

Neurological Disorders ◽

Mammalian Cells ◽

Morphological Changes ◽

Mitochondrial Fission ◽

Gene Mutations ◽

Current Understanding ◽

Mitochondrial Morphology ◽

Cell Death Pathways ◽

Mitochondrial Distribution

Abstract It is now appreciated that mitochondria form tubular networks that adapt to the requirements of the cell by undergoing changes in their shape through fission and fusion. Proper mitochondrial distribution also appears to be required for ATP delivery and calcium regulation, and, in some cases, for cell development. While we now realise the great importance of mitochondria for the cell, we are only beginning to work out how these organelles undergo the drastic morphological changes that are essential for cellular function. Of the few known components involved in shaping mitochondria, some have been found to be essential to life and their gene mutations are linked to neurological disorders, while others appear to be recruited in the activation of cell death pathways. Here we review our current understanding of the functions of the main players involved in mitochondrial fission, fusion and distribution in mammalian cells.

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Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1607152113 ◽

2016 ◽

Vol 113 (44) ◽

pp. E6806-E6812 ◽

Cited By ~ 101

Author(s):

Yang Ou ◽

Shang-Jui Wang ◽

Dawei Li ◽

Bo Chu ◽

Wei Gu

Keyword(s):

Cell Death ◽

Metabolic Pathways ◽

Cell Metabolism ◽

Specific Inhibitor ◽

Polyamine Metabolism ◽

Cycle Arrest ◽

Induced Stress ◽

Rate Limiting ◽

Insight Into

Although p53-mediated cell-cycle arrest, senescence, and apoptosis remain critical barriers to cancer development, the emerging role of p53 in cell metabolism, oxidative responses, and ferroptotic cell death has been a topic of great interest. Nevertheless, it is unclear how p53 orchestrates its activities in multiple metabolic pathways into tumor suppressive effects. Here, we identified the SAT1 (spermidine/spermine N1-acetyltransferase 1) gene as a transcription target of p53. SAT1 is a rate-limiting enzyme in polyamine catabolism critically involved in the conversion of spermidine and spermine back to putrescine. Surprisingly, we found that activation of SAT1 expression induces lipid peroxidation and sensitizes cells to undergo ferroptosis upon reactive oxygen species (ROS)-induced stress, which also leads to suppression of tumor growth in xenograft tumor models. Notably, SAT1 expression is down-regulated in human tumors, and CRISPR-cas9–mediated knockout of SAT1 expression partially abrogates p53-mediated ferroptosis. Moreover, SAT1 induction is correlated with the expression levels of arachidonate 15-lipoxygenase (ALOX15), and SAT1-induced ferroptosis is significantly abrogated in the presence of PD146176, a specific inhibitor of ALOX15. Thus, our findings uncover a metabolic target of p53 involved in ferroptotic cell death and provide insight into the regulation of polyamine metabolism and ferroptosis-mediated tumor suppression.

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Partial prion cross-seeding between fungal and mammalian amyloid signaling motifs

10.1101/2020.07.22.215483 ◽

2020 ◽

Author(s):

Thierry Bardin ◽

Asen Daskalov ◽

Sophie Barrouilhet ◽

Alexandra Granger-Farbos ◽

Bénédicte Salin ◽

...

Keyword(s):

Cell Death ◽

Filamentous Fungi ◽

Sequence Similarity ◽

Podospora Anserina ◽

Cell Death Pathways ◽

Prion Propagation ◽

Cell Death Signaling ◽

Signaling Modules ◽

Β Sheet

AbstractIn filamentous fungi, NLR-based signalosomes activate downstream membrane-targeting cell-death inducing proteins by a mechanism of amyloid templating. In the species Podospora anserina, two such signalosomes, NWD2/HET-S and FNT1/HELLF have been described. An analogous system, involving a distinct amyloid signaling motif termed PP was also identified in the genome of the species Chaetomium globosum and studied using heterologous expression in Podospora anserina. The PP-motif bears resemblance to the RHIM and RHIM-like motifs controlling necroptosis in mammals and innate immunity in flies. We identified here, a third NLR signalosome in Podospora anserina comprising a PP-motif and organized as a two-gene cluster encoding a NLR and a HELL-domain cell-death execution protein termed HELLP. We show that the PP-motif region of HELLP forms a prion we term [π] and that [π] prions trigger the cell-death inducing activity of full length HELLP. We detect no prion cross-seeding between HET-S, HELLF and HELLP amyloid motifs. In addition, we find that akin to PP-motifs, RHIM motifs from human RIP1 and RIP3 kinases are able to form prions in Podospora, and that [π] and [Rhim] prions partially cross-seed. Our study shows that Podospora anserina displays three independent cell-death inducing amyloid signalosomes. Based on the described functional similarity between RHIM and PP, it appears likely that these amyloid motifs constitute evolutionary related cell-death signaling modules.ImportanceAmyloids are β-sheet-rich protein polymers that can be pathological or display a variety of biological roles. In filamentous fungi, specific immune receptors activate programmed cell-death execution proteins through a process of amyloid templating akin to prion propagation.Among these fungal amyloid signaling sequences, the PP-motif stands out because it shows similarity to RHIM, an amyloid sequence controlling necroptotic cell-death in mammals. We characterized an amyloid signaling system comprising a PP-motif in the model species Podospora anserina thus bringing to three the number of independent amyloid signaling cell death pathways described in that species. We then show that human RHIM motifs not only propagate as prions in P. anserina but also partially cross-seed with fungal PP-prions. These results indicate that in addition to show sequence similarity, PP and RHIM-motif are at least partially functionally related, supporting a model of long-term evolutionary conservation of amyloid signaling mechanisms from fungi to mammals.

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Diversity of cell death signaling pathways in macrophages upon infection with modified vaccinia virus Ankara (MVA)

Cell Death and Disease ◽

10.1038/s41419-021-04286-3 ◽

2021 ◽

Vol 12 (11) ◽

Author(s):

Lioba Klaas ◽

Juliane Vier ◽

Ian E. Gentle ◽

Georg Häcker ◽

Susanne Kirschnek

Keyword(s):

Cell Death ◽

Vaccinia Virus ◽

Signaling Pathways ◽

Target Cells ◽

Specific Cell ◽

Substantial Impact ◽

Cell Death Pathways ◽

Modified Vaccinia Virus Ankara ◽

Cell Death Signaling ◽

Induced Apoptosis

AbstractRegulated cell death frequently occurs upon infection by intracellular pathogens, and extent and regulation is often cell-type-specific. We aimed to identify the cell death-signaling pathways triggered in macrophages by infection with modified vaccinia virus Ankara (MVA), an attenuated strain of vaccinia virus used in vaccination. While most target cells seem to be protected by antiapoptotic proteins encoded in the MVA genome, macrophages die when infected with MVA. We targeted key signaling components of specific cell death-pathways and pattern recognition-pathways using genome editing and small molecule inhibitors in an in vitro murine macrophage differentiation model. Upon infection with MVA, we observed activation of mitochondrial and death-receptor-induced apoptosis-pathways as well as the necroptosis-pathway. Inhibition of individual pathways had a little protective effect but led to compensatory death through the other pathways. In the absence of mitochondrial apoptosis, autocrine/paracrine TNF-mediated apoptosis and, in the absence of caspase-activity, necroptosis occurred. TNF-induction depended on the signaling molecule STING, and MAVS and ZBP1 contributed to MVA-induced apoptosis. The mode of cell death had a substantial impact on the cytokine response of infected cells, indicating that the immunogenicity of a virus may depend not only on its PAMPs but also on its ability to modulate individual modalities of cell death. These findings provide insights into the diversity of cell death-pathways that an infection can trigger in professional immune cells and advance our understanding of the intracellular mechanisms that govern the immune response to a virus.

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Methamphetamine Increases the Proportion of SIV-Infected Microglia/Macrophages, Alters Metabolic Pathways, and Elevates Cell Death Pathways: A Single-Cell Analysis

Viruses ◽

10.3390/v12111297 ◽

2020 ◽

Vol 12 (11) ◽

pp. 1297

Author(s):

Meng Niu ◽

Brenda Morsey ◽

Benjamin G. Lamberty ◽

Katy Emanuel ◽

Fang Yu ◽

...

Keyword(s):

Cell Death ◽

Hiv Infection ◽

Single Cell ◽

Metabolic Pathways ◽

Drugs Of Abuse ◽

Expression Patterns ◽

Cns Infection ◽

Brain Macrophages ◽

Cell Death Pathways ◽

The Brain

Both substance use disorder and HIV infection continue to affect many individuals. Both have untoward effects on the brain, and the two conditions often co-exist. In the brain, macrophages and microglia are infectable by HIV, and these cells are also targets for the effects of drugs of abuse, such as the psychostimulant methamphetamine. To determine the interaction of HIV and methamphetamine, we isolated microglia and brain macrophages from SIV-infected rhesus monkeys that were treated with or without methamphetamine. Cells were subjected to single-cell RNA sequencing and results were analyzed by statistical and bioinformatic analysis. In the animals treated with methamphetamine, a significantly increased proportion of the microglia and/or macrophages were infected by SIV. In addition, gene encoding functions in cell death pathways were increased, and the brain-derived neurotropic factor pathway was inhibited. The gene expression patterns in infected cells did not cluster separately from uninfected cells, but clusters comprised of microglia and/or macrophages from methamphetamine-treated animals differed in neuroinflammatory and metabolic pathways from those comprised of cells from untreated animals. Methamphetamine increases CNS infection by SIV and has adverse effects on both infected and uninfected microglia and brain macrophages, highlighting the dual and interacting harms of HIV infection and drug abuse on the brain.

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Inhibition of Macroautophagy Triggers Apoptosis

Molecular and Cellular Biology ◽

10.1128/mcb.25.3.1025-1040.2005 ◽

2005 ◽

Vol 25 (3) ◽

pp. 1025-1040 ◽

Cited By ~ 1129

Author(s):

Patricia Boya ◽

Rosa-Ana González-Polo ◽

Noelia Casares ◽

Jean-Luc Perfettini ◽

Philippe Dessen ◽

...

Keyword(s):

Cell Death ◽

Mammalian Cells ◽

Culture Conditions ◽

Ultrastructural Studies ◽

Cell Death Pathways ◽

Caspase Inhibition ◽

Rna Targeting ◽

Interfering Rna

ABSTRACT Mammalian cells were observed to die under conditions in which nutrients were depleted and, simultaneously, macroautophagy was inhibited either genetically (by a small interfering RNA targeting Atg5, Atg6/Beclin 1-1, Atg10, or Atg12) or pharmacologically (by 3-methyladenine, hydroxychloroquine, bafilomycin A1, or monensin). Cell death occurred through apoptosis (type 1 cell death), since it was reduced by stabilization of mitochondrial membranes (with Bcl-2 or vMIA, a cytomegalovirus-derived gene) or by caspase inhibition. Under conditions in which the fusion between lysosomes and autophagosomes was inhibited, the formation of autophagic vacuoles was enhanced at a preapoptotic stage, as indicated by accumulation of LC3-II protein, ultrastructural studies, and an increase in the acidic vacuolar compartment. Cells exhibiting a morphology reminiscent of (autophagic) type 2 cell death, however, recovered, and only cells with a disrupted mitochondrial transmembrane potential were beyond the point of no return and inexorably died even under optimal culture conditions. All together, these data indicate that autophagy may be cytoprotective, at least under conditions of nutrient depletion, and point to an important cross talk between type 1 and type 2 cell death pathways.

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Oxidants, Antioxidants and Thiol Redox Switches in the Control of Regulated Cell Death Pathways

Antioxidants ◽

10.3390/antiox9040309 ◽

2020 ◽

Vol 9 (4) ◽

pp. 309 ◽

Cited By ~ 7

Author(s):

Moran Benhar

Keyword(s):

Cell Death ◽

Mammalian Cells ◽

Molecular Mechanisms ◽

Nitrosative Stress ◽

Neurological Diseases ◽

Antioxidant Systems ◽

Cell Death Pathways ◽

Regulated Cell Death ◽

Thiol Redox ◽

Redox Switches

It is well appreciated that biological reactive oxygen and nitrogen species such as hydrogen peroxide, superoxide and nitric oxide, as well as endogenous antioxidant systems, are important modulators of cell survival and death in diverse organisms and cell types. In addition, oxidative stress, nitrosative stress and dysregulated cell death are implicated in a wide variety of pathological conditions, including cancer, cardiovascular and neurological diseases. Therefore, much effort is devoted to elucidate the molecular mechanisms linking oxidant/antioxidant systems and cell death pathways. This review is focused on thiol redox modifications as a major mechanism by which oxidants and antioxidants influence specific regulated cell death pathways in mammalian cells. Growing evidence indicates that redox modifications of cysteine residues in proteins are involved in the regulation of multiple cell death modalities, including apoptosis, necroptosis and pyroptosis. In addition, recent research suggests that thiol redox switches play a role in the crosstalk between apoptotic and necrotic forms of regulated cell death. Thus, thiol-based redox circuits provide an additional layer of control that determines when and how cells die.

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Mutagenic Consequences of Sublethal Cell Death Signaling

International Journal of Molecular Sciences ◽

10.3390/ijms22116144 ◽

2021 ◽

Vol 22 (11) ◽

pp. 6144

Author(s):

Christine J. Hawkins ◽

Mark A. Miles

Keyword(s):

Dna Damage ◽

Cell Death ◽

Cancer Cells ◽

Apoptotic Cell ◽

Oncogenic Potential ◽

Genomic Changes ◽

Cell Death Pathways ◽

Anti Cancer ◽

Cell Death Signaling ◽

Mechanisms Of Mutagenesis

Many human cancers exhibit defects in key DNA damage response elements that can render tumors insensitive to the cell death-promoting properties of DNA-damaging therapies. Using agents that directly induce apoptosis by targeting apoptotic components, rather than relying on DNA damage to indirectly stimulate apoptosis of cancer cells, may overcome classical blocks exploited by cancer cells to evade apoptotic cell death. However, there is increasing evidence that cells surviving sublethal exposure to classical apoptotic signaling may recover with newly acquired genomic changes which may have oncogenic potential, and so could theoretically spur the development of subsequent cancers in cured patients. Encouragingly, cells surviving sublethal necroptotic signaling did not acquire mutations, suggesting that necroptosis-inducing anti-cancer drugs may be less likely to trigger therapy-related cancers. We are yet to develop effective direct inducers of other cell death pathways, and as such, data regarding the consequences of cells surviving sublethal stimulation of those pathways are still emerging. This review details the currently known mutagenic consequences of cells surviving different cell death signaling pathways, with implications for potential oncogenic transformation. Understanding the mechanisms of mutagenesis associated (or not) with various cell death pathways will guide us in the development of future therapeutics to minimize therapy-related side effects associated with DNA damage.

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