scholarly journals Impaired lysosomal acidification triggers iron deficiency, necrotic cell death and inflammationin vivo

2019 ◽  
Author(s):  
King Faisal Yambire ◽  
Christine Rostosky ◽  
Takashi Watanabe ◽  
David Pacheu-Grau ◽  
Sylvia Torres-Odio ◽  
...  
Keyword(s):  
Cell Death ◽  
Iron Deficiency ◽  
Necrotic Cell Death ◽  
Primary Neurons ◽  
Resonance Imaging ◽  
Necrotic Cell ◽  
Cellular Iron ◽  
The Brain ◽  
Lysosomal Acidification

SUMMARYLysosomal acidification is a key feature of healthy cells. Inability to maintain lysosomal acidic pH is associated with aging and neurodegenerative diseases. However, the mechanisms elicited by impaired lysosomal acidification remain unknown. We show here that inhibition of lysosomal acidification triggers cellular iron deficiency, which results in impaired mitochondrial function and necrotic cell death. These effects are recovered by supplying iron via a lysosome-independent pathway. Notably, iron deficiency is sufficient to trigger inflammatory signaling in cultured primary neurons. Using a mouse model of impaired lysosomal acidification, we observed a robust iron deficiency response in the brain, verified byin vivomagnetic resonance imaging. Furthermore, the brains of these mice present a pervasive inflammatory signature associated with instability of mitochondrial DNA (mtDNA), both corrected by supplementation of the mice diet with iron. Our results highlight a novel mechanism linking lysosomal dysfunction, mitochondrial malfunction and inflammationin vivo.

scholarly journals Impaired lysosomal acidification triggers iron deficiency and inflammation in vivo

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
King Faisal Yambire ◽  
Christine Rostosky ◽  
Takashi Watanabe ◽  
David Pacheu-Grau ◽  
Sylvia Torres-Odio ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Apoptotic Cell ◽  
Primary Neurons ◽  
Acidic Ph ◽  
Resonance Imaging ◽  
Inflammatory Signaling ◽  
Cellular Iron ◽  
The Brain ◽  
Lysosomal Acidification

Lysosomal acidification is a key feature of healthy cells. Inability to maintain lysosomal acidic pH is associated with aging and neurodegenerative diseases. However, the mechanisms elicited by impaired lysosomal acidification remain poorly understood. We show here that inhibition of lysosomal acidification triggers cellular iron deficiency, which results in impaired mitochondrial function and non-apoptotic cell death. These effects are recovered by supplying iron via a lysosome-independent pathway. Notably, iron deficiency is sufficient to trigger inflammatory signaling in cultured primary neurons. Using a mouse model of impaired lysosomal acidification, we observed a robust iron deficiency response in the brain, verified by in vivo magnetic resonance imaging. Furthermore, the brains of these mice present a pervasive inflammatory signature associated with instability of mitochondrial DNA (mtDNA), both corrected by supplementation of the mice diet with iron. Our results highlight a novel mechanism linking impaired lysosomal acidification, mitochondrial malfunction and inflammation in vivo.

Determination of apoptotic and necrotic cell death in vitro and in vivo

Methods ◽  
2013 ◽  
Vol 61 (2) ◽  
pp. 117-129 ◽  
Author(s):  
Tom Vanden Berghe ◽  
Sasker Grootjans ◽  
Vera Goossens ◽  
Yves Dondelinger ◽  
Dmitri V. Krysko ◽  
...  
Keyword(s):  
Cell Death ◽  
Necrotic Cell Death ◽  
Necrotic Cell

Abstract 23: Disruption of TRAF2-TAK1-NF-κB Signaling Axis Triggers K-48 Linked Poly-Ubiquitylation of RIP1 and Necrotic Cell Death in Doxorubicin Cardiotoxicity

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Rimpy Dhingra ◽  
Victoria Margulets ◽  
Floribeth Aguilar ◽  
Lorrie A. Kirshenbaum
Keyword(s):  
Cell Death ◽  
Cardiac Myocytes ◽  
Cell Injury ◽  
Ventricular Myocytes ◽  
Necrotic Cell Death ◽  
Ros Production ◽  
Necrotic Cell ◽  
Interacting Protein

The anthracycline doxorubicin (Dox) is a highly effective anti-tumour agent, however, its use is limited by its severe cardiotoxic effects that manifests as heart failure. The decline in cardiac performance induced by doxorubicin remains poorly defined. A critical survival role for the canonical IKKβ -mTOR-NF-κB signaling pathway has been demonstrated in ventricular myocytes. In this report, we demonstrate that, Dox impairs IKKβ-mTOR- NF-κB signaling in ventricular myocytes accompanied by mitochondrial perturbations including mPTP, loss of mitochondrial membrane potential and ROS production. IKKβ- NF-κB signaling involves TRAF 2 mediated ligation of K63- ubiquitin chains to RIP1 (Receptor Interacting Protein 1) which serves as scaffold for recruitment of ubiquitylated Tak1 complexes and phosphorylation-dependent activation of IKKβ -NF-kB signaling. Interestingly, ventricular myocytes treated with dox demonstrated reduction in expression levels of TRAF2 and TAK1, in vivo and in vitro. This was accompanied by a decline in K63- and concomitant increase in K-48 linked polyubiquitination on RIP1, impaired NF-kB activation and necrotic cell death of cardiac myocytes. Interestingly, inhibiting the kinase activity of RIP1 with Necrostatin-1, (Nec1) suppressed necrotic cell injury induced by dox but not NF-kB activation. Concordant with these findings was a marked increase in necrotic cell death in cardiac myocytes defective for IKKB signaling or MEF cells deficient for p65 treated with dox. Notably, mitochondrial perturbations, including PT-pore opening , ROS production, calcium uptake, LDH, Tn(T) and HMGB-1 release and necrotic cell injury induced by dox were completely abrogated by restoring NF-kB signaling in cardiac myocytes or Nec-1. Herein, we provide novel evidence that K-48 linked poly ubiquitylation of RIP1 provides a functional switch that impairs NF-kB activation and signals necrosis in cells treated with dox. Interventions that modulate NF-kB activity may prove beneficial in mitigating the cardiotoxic effects of dox.

scholarly journals P. aeruginosa Mediated Necroptosis in Mouse Tumor Cells Induces Long-Lasting Systemic Antitumor Immunity

2021 ◽  
Vol 10 ◽  
Author(s):  
Jia-long Qi ◽  
Jin-rong He ◽  
Shu-mei Jin ◽  
Xu Yang ◽  
Hong-mei Bai ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Tumor Response ◽  
Necrotic Cell Death ◽  
Immunogenic Cell Death ◽  
Mouse Tumor ◽  
Necrotic Cell ◽  
Tumor Cell Death

Necroptosis is a form of programmed cell death (PCD) characterized by RIP3 mediated MLKL activation and increased membrane permeability via MLKL oligomerization. Tumor cell immunogenic cell death (ICD) has been considered to be essential for the anti-tumor response, which is associated with DC recruitment, activation, and maturation. In this study, we found that P. aeruginosa showed its potential to suppress tumor growth and enable long-lasting anti-tumor immunity in vivo. What’s more, phosphorylation- RIP3 and MLKL activation induced by P. aeruginosa infection resulted in tumor cell necrotic cell death and HMGB1 production, indicating that P. aeruginosa can cause immunogenic cell death. The necrotic cell death can further drive a robust anti-tumor response via promoting tumor cell death, inhibiting tumor cell proliferation, and modulating systemic immune responses and local immune microenvironment in tumor. Moreover, dying tumor cells killed by P. aeruginosa can catalyze DC maturation, which enhanced the antigen-presenting ability of DC cells. These findings demonstrate that P. aeruginosa can induce immunogenic cell death and trigger a robust long-lasting anti-tumor response along with reshaping tumor microenvironment.

scholarly journals Rosemary (Rosmarinus officinalis) extract causes ROS-induced necrotic cell death and inhibits tumor growth in vivo

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Almudena Pérez-Sánchez ◽  
Enrique Barrajón-Catalán ◽  
Verónica Ruiz-Torres ◽  
Luz Agulló-Chazarra ◽  
María Herranz-López ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Growth ◽  
Rosmarinus Officinalis ◽  
Necrotic Cell Death ◽  
Necrotic Cell

scholarly journals A major role for ferroptosis in Mycobacterium tuberculosis–induced cell death and tissue necrosis

2019 ◽  
Vol 216 (3) ◽  
pp. 556-570 ◽  
Author(s):  
Eduardo P. Amaral ◽  
Diego L. Costa ◽  
Sivaranjani Namasivayam ◽  
Nicolas Riteau ◽  
Olena Kamenyeva ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Mycobacterium Tuberculosis ◽  
Bacterial Load ◽  
Lipid Peroxides ◽  
Necrotic Cell Death ◽  
Necrotic Cell ◽  
Free Iron ◽  
Regulated Necrosis

Necrotic cell death during Mycobacterium tuberculosis (Mtb) infection is considered host detrimental since it facilitates mycobacterial spread. Ferroptosis is a type of regulated necrosis induced by accumulation of free iron and toxic lipid peroxides. We observed that Mtb-induced macrophage necrosis is associated with reduced levels of glutathione and glutathione peroxidase-4 (Gpx4), along with increased free iron, mitochondrial superoxide, and lipid peroxidation, all of which are important hallmarks of ferroptosis. Moreover, necrotic cell death in Mtb-infected macrophage cultures was suppressed by ferrostatin-1 (Fer-1), a well-characterized ferroptosis inhibitor, as well as by iron chelation. Additional experiments in vivo revealed that pulmonary necrosis in acutely infected mice is associated with reduced Gpx4 expression as well as increased lipid peroxidation and is likewise suppressed by Fer-1 treatment. Importantly, Fer-1–treated infected animals also exhibited marked reductions in bacterial load. Together, these findings implicate ferroptosis as a major mechanism of necrosis in Mtb infection and as a target for host-directed therapy of tuberculosis.

scholarly journals Necroptosis and apoptosis contribute to cisplatin and aminoglycoside ototoxicity

2018 ◽  
Author(s):  
Douglas Ruhl ◽  
Ting-Ting Du ◽  
Jeong-Hwan Choi ◽  
Sihan Li ◽  
Robert Reed ◽  
...  
Keyword(s):  
Cell Death ◽  
Side Effects ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Necrotic Cell Death ◽  
Necrotic Cell ◽  
Genetic Intervention ◽  
Aminoglycoside Ototoxicity ◽  
Cell Death Pathway

AbstractOtotoxic side effects of cisplatin and aminoglycosides have been extensively studied, but no therapy is available to date. Sensory hair cells, upon exposure to cisplatin or aminoglycosides, undergo apoptotic and necrotic cell death. Blocking these cell death pathways has therapeutic potential in theory, but incomplete protection and lack of therapeutic targets in the case of necrosis, has hampered the development of clinically applicable drugs. Over the past decade, a novel form of necrosis, termed necroptosis, was established as an alternative cell death pathway. Necroptosis is distinguished from passive necrotic cell death, in that it follows a cellular program, involving the receptor-interacting protein kinases 1 and 3 (RIPK1 and 3). In this study, we used pharmacological and genetic intervention to test the relative contributions of necroptosis and caspase-8-mediated apoptosis towards cisplatin and aminoglycoside ototoxicity. We find that ex vivo, only apoptosis contributes to cisplatin and aminoglycoside ototoxicity, while in vivo, both necroptosis and apoptosis are involved. Inhibition of necroptosis and apoptosis using pharmacological compounds is thus a viable strategy to ameliorate aminoglycoside and cisplatin ototoxicity.Significance statementThe clinical application of cisplatin and aminoglycosides is limited due to ototoxic side effects. Here, using pharmaceutical and genetic intervention, we present evidence that two types of programmed cell death, apoptosis and necroptosis, contribute to aminoglycoside and cisplatin ototoxicity. Key molecular factors mediating necroptosis are well characterized and druggable, presenting new avenues for pharmaceutical intervention.

scholarly journals Origin and Consequences of Necroinflammation

2018 ◽  
Vol 98 (2) ◽  
pp. 727-780 ◽  
Author(s):  
Maysa Sarhan ◽  
Walter G. Land ◽  
Wulf Tonnus ◽  
Christian P. Hugo ◽  
Andreas Linkermann
Keyword(s):  
Cell Death ◽  
Immune System ◽  
Current Knowledge ◽  
Necrotic Cell Death ◽  
Necrotic Cell ◽  
Relative Contribution ◽  
Regulated Necrosis ◽  
Genetically Determined ◽  
Molecular Patterns

When cells undergo necrotic cell death in either physiological or pathophysiological settings in vivo, they release highly immunogenic intracellular molecules and organelles into the interstitium and thereby represent the strongest known trigger of the immune system. With our increasing understanding of necrosis as a regulated and genetically determined process (RN, regulated necrosis), necrosis and necroinflammation can be pharmacologically prevented. This review discusses our current knowledge about signaling pathways of necrotic cell death as the origin of necroinflammation. Multiple pathways of RN such as necroptosis, ferroptosis, and pyroptosis have been evolutionary conserved most likely because of their differences in immunogenicity. As the consequence of necrosis, however, all necrotic cells release damage associated molecular patterns (DAMPs) that have been extensively investigated over the last two decades. Analysis of necroinflammation allows characterizing specific signatures for each particular pathway of cell death. While all RN-pathways share the release of DAMPs in general, most of them actively regulate the immune system by the additional expression and/or maturation of either pro- or anti-inflammatory cytokines/chemokines. In addition, DAMPs have been demonstrated to modulate the process of regeneration. For the purpose of better understanding of necroinflammation, we introduce a novel classification of DAMPs in this review to help detect the relative contribution of each RN-pathway to certain physiological and pathophysiological conditions.

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