Gasdermin D mediates host cell death but not interleukin-1β secretion in Mycobacterium tuberculosis-infected macrophages

AbstractNecrotic cell death represents a major pathogenic mechanism of Mycobacterium tuberculosis (Mtb) infection. It is increasingly evident that Mtb induces several types of regulated necrosis but how these are interconnected and linked to the release of pro-inflammatory cytokines remains unknown. Exploiting a clinical cohort of tuberculosis patients, we show here that the number and size of necrotic lesions correlates with IL-1β plasma levels as a strong indicator of inflammasome activation. Our mechanistic studies reveal that Mtb triggers mitochondrial permeability transition (mPT) and subsequently extensive macrophage necrosis, which requires activation of the NLRP3 inflammasome. NLRP3-driven mitochondrial damage is dependent on proteolytic activation of the pore-forming effector protein gasdermin D (GSDMD), which links two distinct cell death machineries. Intriguingly, GSDMD, but not the membranolytic mycobacterial ESX-1 secretion system, is dispensable for IL-1β secretion from Mtb-infected macrophages. Thus, our study dissects a novel mechanism of pathogen-induced regulated necrosis by identifying mitochondria as central regulatory hubs capable of delineating cytokine secretion and lytic cell death.

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Cell Death in the Kidney

International Journal of Molecular Sciences ◽

10.3390/ijms20143598 ◽

2019 ◽

Vol 20 (14) ◽

pp. 3598 ◽

Cited By ~ 13

Author(s):

Giovanna Priante ◽

Lisa Gianesello ◽

Monica Ceol ◽

Dorella Del Prete ◽

Franca Anglani

Keyword(s):

Cell Death ◽

Mitochondrial Permeability Transition ◽

Apoptotic Cell ◽

Parenchymal Cell ◽

Kidney Injury ◽

Permeability Transition ◽

Cell Loss ◽

Relative Contribution ◽

Regulated Cell Death ◽

Regulated Necrosis

Apoptotic cell death is usually a response to the cell’s microenvironment. In the kidney, apoptosis contributes to parenchymal cell loss in the course of acute and chronic renal injury, but does not trigger an inflammatory response. What distinguishes necrosis from apoptosis is the rupture of the plasma membrane, so necrotic cell death is accompanied by the release of unprocessed intracellular content, including cellular organelles, which are highly immunogenic proteins. The relative contribution of apoptosis and necrosis to injury varies, depending on the severity of the insult. Regulated cell death may result from immunologically silent apoptosis or from immunogenic necrosis. Recent advances have enhanced the most revolutionary concept of regulated necrosis. Several modalities of regulated necrosis have been described, such as necroptosis, ferroptosis, pyroptosis, and mitochondrial permeability transition-dependent regulated necrosis. We review the different modalities of apoptosis, necrosis, and regulated necrosis in kidney injury, focusing particularly on evidence implicating cell death in ectopic renal calcification. We also review the evidence for the role of cell death in kidney injury, which may pave the way for new therapeutic opportunities.

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Functions of BCL-XLat the Interface between Cell Death and Metabolism

International Journal of Cell Biology ◽

10.1155/2013/705294 ◽

2013 ◽

Vol 2013 ◽

pp. 1-10 ◽

Cited By ~ 51

Author(s):

Judith Michels ◽

Oliver Kepp ◽

Laura Senovilla ◽

Delphine Lissa ◽

Maria Castedo ◽

...

Keyword(s):

Cell Death ◽

Mitochondrial Permeability Transition ◽

Atp Synthesis ◽

Anion Channel ◽

Permeability Transition ◽

Short Review ◽

Mitochondrial Outer Membrane ◽

Voltage Dependent Anion Channel ◽

Regulated Necrosis ◽

Voltage Dependent

The BCL-2 homolog BCL-XL, one of the two protein products ofBCL2L1, has originally been characterized for its prominent prosurvival functions. Similar to BCL-2, BCL-XLbinds to its multidomain proapoptotic counterparts BAX and BAK, hence preventing the formation of lethal pores in the mitochondrial outer membrane, as well as to multiple BH3-only proteins, thus interrupting apical proapoptotic signals. In addition, BCL-XLhas been suggested to exert cytoprotective functions by sequestering a cytosolic pool of the pro-apoptotic transcription factor p53 and by binding to the voltage-dependent anion channel 1 (VDAC1), thereby inhibiting the so-called mitochondrial permeability transition (MPT). Thus, BCL-XLappears to play a prominent role in the regulation of multiple distinct types of cell death, including apoptosis and regulated necrosis. More recently, great attention has been given to the cell death-unrelated functions of BCL-2-like proteins. In particular, BCL-XLhas been shown to modulate a number of pathophysiological processes, including—but not limited to—mitochondrial ATP synthesis, protein acetylation, autophagy and mitosis. In this short review article, we will discuss the functions of BCL-XLat the interface between cell death and metabolism.

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Abstract 173: The Role of Bax and Bak in Autophagic Cell Death

Circulation Research ◽

10.1161/res.117.suppl_1.173 ◽

2015 ◽

Vol 117 (suppl_1) ◽

Author(s):

Jason Karch ◽

Tobias G Schips ◽

Matthew J Brody ◽

Onur Kanisicak ◽

Michelle A Sargent ◽

...

Keyword(s):

Cell Death ◽

Membrane Permeability ◽

Mitochondrial Permeability Transition ◽

Permeability Transition ◽

Autophagic Cell Death ◽

Serum Starvation ◽

Cytochrome C Release ◽

Energy Depletion ◽

Regulated Necrosis

In times of energy depletion, a cell will attempt to maintain metabolic homeostasis and viability by degrading and recycling organelles and intracellular components and proteins in a process referred to as autophagy. However, if the energy depletion persists, the cell will be overwhelmed by the autophagic process and will succumb to autophagic cell death. This form of cell death has been implicated in cardiac remodeling during heart failure and damage during ischemic injury. Two proteins that have been previously shown to play a role in virtually every form of regulated cell death, including autophagy, are Bax and Bak. These effectors are responsible for cytochrome-c release during apoptosis and effect mitochondrial permeability transition pore opening during regulated necrosis. Although the expression of either Bax or Bak is required for autophagic cell death to occur, the role of Bax/Bak in this type of cell death is poorly understood, although the lysosome appears to be centrally involved. Here we show that Bax/Bak DKO MEFs subjected to several days of serum starvation contain intact lysosomes compared to WT MEFs. Furthermore, the acidity of the lysosomes in starved DKO MEFs is preserved compared with starved WT MEFs. Bax and Bak are both found in isolated lysosomal preparations and Bax targeted to the lysosome can completely restore autophagic cell death in DKO MEFs. Finally, although Bax oligomerization is required for apoptosis, it is not necessary for autophagic cell death, as DKO MEFs expressing an oligomerization defective mutant of Bax are still susceptible to this form of death, as monomeric Bax can still increase membrane permeability. In conclusion our results suggest that lysosomal membrane permeability through Bax or Bak is required for autophagic cell death to occur and without Bax or Bak the lysosomes remain intact where they can function as an energy source during times of nutrient deprivation.

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Corticosteroids inhibit Mycobacterium tuberculosis-induced necrotic host cell death by abrogating mitochondrial membrane permeability transition

Nature Communications ◽

10.1038/s41467-019-08405-9 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 14

Author(s):

Jessica Gräb ◽

Isabelle Suárez ◽

Edeltraud van Gumpel ◽

Sandra Winter ◽

Fynn Schreiber ◽

...

Keyword(s):

Cell Death ◽

Mycobacterium Tuberculosis ◽

Host Cell ◽

Membrane Permeability ◽

Mitochondrial Membrane ◽

Permeability Transition ◽

Mitochondrial Membrane Permeability ◽

Membrane Permeability Transition ◽

Host Cell Death

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Faculty Opinions recommendation of Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1025130.301711 ◽

2005 ◽

Author(s):

Atan Gross

Keyword(s):

Cell Death ◽

Mitochondrial Permeability Transition ◽

Critical Role ◽

Permeability Transition ◽

Cyclophilin D ◽

Mitochondrial Permeability

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Faculty Opinions recommendation of Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1025130.297852 ◽

2005 ◽

Author(s):

Robert Sapolsky

Keyword(s):

Cell Death ◽

Mitochondrial Permeability Transition ◽

Critical Role ◽

Permeability Transition ◽

Cyclophilin D ◽

Mitochondrial Permeability

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Faculty Opinions recommendation of Phagosomal rupture by Mycobacterium tuberculosis results in toxicity and host cell death.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13988977.15445089 ◽

2012 ◽

Author(s):

Thierry Soldati ◽

Sonia Arafah

Keyword(s):

Cell Death ◽

Mycobacterium Tuberculosis ◽

Host Cell ◽

Host Cell Death

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Metformin induces apoptosis via uterus mitochondrial permeability transition pore opening and protects against estradiol benzoate-induced uterine defect and associated pathophysiological disorder in female Wistar rats

Bulletin of the National Research Centre ◽

10.1186/s42269-021-00562-6 ◽

2021 ◽

Vol 45 (1) ◽

Author(s):

Adeola Oluwakemi Olowofolahan ◽

Obinna Matthew Paulinus ◽

Heritage Mojisola Dare ◽

Olufunso Olabode Olorunsogo

Keyword(s):

Cell Death ◽

Cytochrome C ◽

Mitochondrial Permeability Transition ◽

Permeability Transition ◽

Estradiol Benzoate ◽

Histological Evaluation ◽

Mitochondrial Atpase ◽

Rat Uterus ◽

Mitochondrial Permeability ◽

Pore Opening

Abstract Background Some antitumor or anticancer agents have been shown to execute cell death by induction of mitochondrial permeability transition (mPT) pore opening in order to elicit their chemotherapeutic effect. Therefore, this study investigated the effect of metformin on cell death via rat uterus mPT pore and estradiol benzoate-induced uterine defect and associated pathophysiological disorder in female rat. Mitochondria were isolated using differential centrifugation. The mPT pore opening, cytochrome c release and mitochondrial ATPase activity were determined spectrophotometrically. Caspases 9 and 3 activities, MDA and estradiol levels and SOD, GSH activities, were determined using ELISA technique. Histological and histochemical assessments of the uterine section were carried out using standard methods. Results Metformin at concentrations 10–90 μg/mL, showed no significant effect on mPT pore opening, mATPase activity and release of cytochrome c. However, oral administration of metformin caused mPT pore opening, enhancement of mATPase activity and activation of caspases 9 and 3 significantly at 300 and 400 mg/kg. Metformin protected against estradiol benzoate (EB)-induced uterine defect and other associated pathophysiological disorder. It also improved the antioxidant defense system. The histological evaluation revealed the protective effect of metformin on the cellular architecture of the uterus while the histochemical examination showed severe hyperplasia in the uterine section of EB-treated rats, remarkably reversed by metformin co-treatment. Conclusion This study suggests that metformin at high doses induces apoptosis via rat uterus mPT pore opening and protects against EB-induced uterine defect (hyperplasia) and associated pathophysiological disorder.

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Mitochondria and Pharmacologic Cardiac Conditioning—At the Heart of Ischemic Injury

International Journal of Molecular Sciences ◽

10.3390/ijms22063224 ◽

2021 ◽

Vol 22 (6) ◽

pp. 3224

Author(s):

Christopher Lotz ◽

Johannes Herrmann ◽

Quirin Notz ◽

Patrick Meybohm ◽

Franz Kehl

Keyword(s):

Cell Death ◽

Mitochondrial Permeability Transition ◽

Permeability Transition ◽

Research Field ◽

Calcium Handling ◽

Control Mechanisms ◽

Intrinsic Resistance ◽

Atp Production ◽

Cardiac Conditioning ◽

A Cell

Pharmacologic cardiac conditioning increases the intrinsic resistance against ischemia and reperfusion (I/R) injury. The cardiac conditioning response is mediated via complex signaling networks. These networks have been an intriguing research field for decades, largely advancing our knowledge on cardiac signaling beyond the conditioning response. The centerpieces of this system are the mitochondria, a dynamic organelle, almost acting as a cell within the cell. Mitochondria comprise a plethora of functions at the crossroads of cell death or survival. These include the maintenance of aerobic ATP production and redox signaling, closely entwined with mitochondrial calcium handling and mitochondrial permeability transition. Moreover, mitochondria host pathways of programmed cell death impact the inflammatory response and contain their own mechanisms of fusion and fission (division). These act as quality control mechanisms in cellular ageing, release of pro-apoptotic factors and mitophagy. Furthermore, recently identified mechanisms of mitochondrial regeneration can increase the capacity for oxidative phosphorylation, decrease oxidative stress and might help to beneficially impact myocardial remodeling, as well as invigorate the heart against subsequent ischemic insults. The current review highlights different pathways and unresolved questions surrounding mitochondria in myocardial I/R injury and pharmacological cardiac conditioning.

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