Cofilin1 oxidation links oxidative distress to mitochondrial demise and neuronal cell death

AbstractMany cell death pathways, including apoptosis, regulated necrosis, and ferroptosis, are relevant for neuronal cell death and share common mechanisms such as the formation of reactive oxygen species (ROS) and mitochondrial damage. Here, we present the role of the actin-regulating protein cofilin1 in regulating mitochondrial pathways in oxidative neuronal death. Cofilin1 deletion in neuronal HT22 cells exerted increased mitochondrial resilience, assessed by quantification of mitochondrial ROS production, mitochondrial membrane potential, and ATP levels. Further, cofilin1-deficient cells met their energy demand through enhanced glycolysis, whereas control cells were metabolically impaired when challenged by ferroptosis. Further, cofilin1 was confirmed as a key player in glutamate-mediated excitotoxicity and associated mitochondrial damage in primary cortical neurons. Using isolated mitochondria and recombinant cofilin1, we provide a further link to toxicity-related mitochondrial impairment mediated by oxidized cofilin1. Our data revealed that the detrimental impact of cofilin1 on mitochondria depends on the oxidation of cysteine residues at positions 139 and 147. Overall, our findings show that cofilin1 acts as a redox sensor in oxidative cell death pathways of ferroptosis, and also promotes glutamate excitotoxicity. Protective effects by cofilin1 inhibition are particularly attributed to preserved mitochondrial integrity and function. Thus, interfering with the oxidation and pathological activation of cofilin1 may offer an effective therapeutic strategy in neurodegenerative diseases.

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Cofilin1 oxidation links oxidative distress to mitochondrial demise and neuronal cell death

10.1101/2020.09.09.289710 ◽

2020 ◽

Author(s):

Lena Hoffmann ◽

Marcel S. Waclawczyk ◽

Eva-Maria Hanschmann ◽

Manuela Gellert ◽

Marco B. Rust ◽

...

Keyword(s):

Cell Death ◽

Membrane Potential ◽

Mitochondrial Respiration ◽

Mitochondrial Membrane ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Ht22 Cells ◽

Cell Death Pathways ◽

Mitochondrial Ros ◽

Ros Accumulation

AbstractMany cell death pathways, including apoptosis, regulated necrosis and ferroptosis are relevant for neuronal cell death and share common mechanisms such as the formation of reactive oxygen species (ROS). However, which molecular signaling pathways contribute to related pathologies and how they are interconnected remains elusive.Here, we present the role of cofilin1 in regulating mitochondrial functions and neuronal impairment. Cofilin1 deletion in neuronal HT22 cells exerted increased mitochondrial resilience, assessed by quantification of mitochondrial ROS production, mitochondrial membrane potential and ATP levels. HT22 cells deficient for cofilin1 exhibited a profound glycolytic shift to meet their energy demand in conditions of erastin and glutamate toxicity, whereas control cells were metabolically impaired and underwent ferroptosis and oxytosis, respectively. Further, cofilin1 was confirmed as a key player in glutamate-mediated excitotoxicity in primary cortical neurons isolated from cofilin1flx/flx, CaMKIIα-Cre knock-out mice. Mitochondrial respiration and cell viability were significantly preserved in cofilin1-/- primary neurons under conditions of excitotoxicity.Using isolated mitochondria and recombinant cofilin1, we provide a further link to toxicity-related mitochondrial impairment mediated by oxidized cofilin1. Wildtype cofilin1 directly affected the mitochondrial membrane potential, mitochondrial ROS accumulation and mitochondrial respiration. The detrimental impact of cofilin1 on mitochondria depends on oxidation of cysteine residues at positions 139 and 147.Our findings show that the actin-regulating protein cofilin1 acts as a redox sensor in oxidative cell death pathways of ferroptosis and oxytosis, and also promotes glutamate excitotoxicity. Oxidized cofilin1 links ROS accumulation to mitochondrial demise and neuronal cell death. Protective effects by cofilin1 inhibition are particularly attributed to preserved mitochondrial integrity and function. Thus, interfering with the oxidation and pathological activation of cofilin1 may offer an effective therapeutic strategy in neurodegenerative diseases.

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Pneumolysin Causes Neuronal Cell Death through Mitochondrial Damage

Infection and Immunity ◽

10.1128/iai.00031-07 ◽

2007 ◽

Vol 75 (9) ◽

pp. 4245-4254 ◽

Cited By ~ 77

Author(s):

Johann S. Braun ◽

Olaf Hoffmann ◽

Miriam Schickhaus ◽

Dorette Freyer ◽

Emilie Dagand ◽

...

Keyword(s):

Cell Death ◽

Caspase 3 ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Mitochondrial Damage ◽

Cell Death Pathways ◽

Apoptosis Protein ◽

Mitochondrial Toxin ◽

Induced Apoptosis ◽

Apoptosis Inducing Factor

ABSTRACT Bacterial toxins such as pneumolysin are key mediators of cytotoxicity in infections. Pneumolysin is a pore-forming toxin released by Streptococcus pneumoniae, the major cause of bacterial meningitis. We found that pneumolysin is the pneumococcal factor that accounts for the cell death pathways induced by live bacteria in primary neurons. The pore-forming activity of pneumolysin is essential for the induction of mitochondrial damage and apoptosis. Pneumolysin colocalized with mitochondrial membranes, altered the mitochondrial membrane potential, and caused the release of apoptosis-inducing factor and cell death. Pneumolysin induced neuronal apoptosis without activating caspase-1, -3, or -8. Wild-type pneumococci also induced apoptosis without activation of caspase-3, whereas pneumolysin-negative pneumococci activated caspase-3 through the release of bacterial hydrogen peroxide. Pneumolysin caused upregulation of X-chromosome-linked inhibitor of apoptosis protein and inhibited staurosporine-induced caspase activation, suggesting the presence of actively suppressive mechanisms on caspases. In conclusion, our results indicate additional functions of pneumolysin as a mitochondrial toxin and as a determinant of caspase-independent apoptosis. Considering this, blocking of pneumolysin may be a promising cytoprotective strategy in pneumococcal meningitis and other infections.

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Ginsenoside Rb2 suppresses the glutamate-mediated oxidative stress and neuronal cell death in HT22 cells

Journal of Ginseng Research ◽

10.1016/j.jgr.2018.12.002 ◽

2019 ◽

Vol 43 (2) ◽

pp. 326-334 ◽

Cited By ~ 19

Author(s):

Dong Hoi Kim ◽

Dae Won Kim ◽

Bo Hyun Jung ◽

Jong Hun Lee ◽

Heesu Lee ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Ht22 Cells ◽

Ginsenoside Rb2

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Neuroprotective Effects of Tetrahydrocurcumin against Glutamate-Induced Oxidative Stress in Hippocampal HT22 Cells

Molecules ◽

10.3390/molecules25010144 ◽

2019 ◽

Vol 25 (1) ◽

pp. 144 ◽

Cited By ~ 4

Author(s):

Chang-Hyun Park ◽

Ji Hoon Song ◽

Su-Nam Kim ◽

Ji Hwan Lee ◽

Hae-Jeung Lee ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Protein Kinases ◽

Apoptotic Cell ◽

Curcuma Longa ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Ht22 Cells ◽

Mitogen Activated Protein Kinases ◽

Mitogen Activated Protein

In the central nervous system, glutamate is a major excitable neurotransmitter responsible for many cellular functions. However, excessive levels of glutamate induce neuronal cell death via oxidative stress during acute brain injuries as well as chronic neurodegenerative diseases. The present study was conducted to examine the effect of tetrahydrocurcumin (THC), a major secondary metabolite of curcumin, and its possible mechanism against glutamate-induced cell death. We prepared THC using curcumin isolated from Curcuma longa (turmeric) and demonstrated the protective effect of THC against glutamate-induced oxidative stress in HT22 cells. THC abrogated glutamate-induced HT22 cell death and showed a strong antioxidant effect. THC also significantly reduced intracellular calcium ion increased by glutamate. Additionally, THC significantly reduced the accumulation of intracellular oxidative stress induced by glutamate. Furthermore, THC significantly diminished apoptotic cell death indicated by annexin V-positive in HT22 cells. Western blot analysis indicated that the phosphorylation of mitogen-activated protein kinases including c-Jun N-terminal kinase, extracellular signal-related kinases 1/2, and p38 by glutamate was significantly diminished by treatment with THC. In conclusion, THC is a potent neuroprotectant against glutamate-induced neuronal cell death by inhibiting the accumulation of oxidative stress and phosphorylation of mitogen-activated protein kinases.

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Peroxiredoxin 5 Inhibits Glutamate-Induced Neuronal Cell Death through the Regulation of Calcineurin-Dependent Mitochondrial Dynamics in HT22 Cells

Molecular and Cellular Biology ◽

10.1128/mcb.00148-19 ◽

2019 ◽

Vol 39 (20) ◽

Cited By ~ 6

Author(s):

Mi Hye Kim ◽

Hong Jun Lee ◽

Sang-Rae Lee ◽

Hyun-Shik Lee ◽

Jae-Won Huh ◽

...

Keyword(s):

Cell Death ◽

Neurodegenerative Diseases ◽

Mitochondrial Dynamics ◽

Mitochondrial Fission ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Glutamate Toxicity ◽

Ht22 Cells ◽

Peroxidase Enzyme ◽

The Central Nervous System

ABSTRACT Glutamate is an essential neurotransmitter in the central nervous system (CNS). However, high glutamate concentrations can lead to neurodegenerative diseases. A hallmark of glutamate toxicity is high levels of reactive oxygen species (ROS), which can trigger Ca2+ influx and dynamin-related protein 1 (Drp1)-mediated mitochondrial fission. Peroxiredoxin 5 (Prx5) is a well-known cysteine-dependent peroxidase enzyme. However, the precise effects of Prx5 on glutamate toxicity are still unclear. In this study, we investigated the role of Prx5 in glutamate-induced neuronal cell death. We found that glutamate treatment induces endogenous Prx5 expression and Ca2+/calcineurin-dependent dephosphorylation of Drp1, resulting in mitochondrial fission and neuronal cell death. Our results indicate that Prx5 inhibits glutamate-induced mitochondrial fission through the regulation of Ca2+/calcineurin-dependent dephosphorylation of Drp1, and it does so by scavenging cytosolic and mitochondrial ROS. Therefore, we suggest that Ca2+/calcineurin-dependent mitochondrial dynamics are deeply associated with glutamate-induced neurotoxicity. Consequently, Prx5 may be used as a potential agent for developing therapies against glutamate-induced neurotoxicity and neurodegenerative diseases where it plays a key role.

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Protective effects of adenosine on apoptotic neuronal cell death in cultured cortical neurons

The Japanese Journal of Pharmacology ◽

10.1016/s0021-5198(19)48190-0 ◽

2000 ◽

Vol 82 ◽

pp. 182

Author(s):

Yutaka Tamura ◽

Taizo Fukui ◽

Megumi Kajikawa ◽

Mikiko Omoto ◽

Hirohito Shiomi

Keyword(s):

Cell Death ◽

Cortical Neurons ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Protective Effects ◽

Cultured Cortical Neurons

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Pyroptotic Neuronal Cell Death Mediated by the AIM2 Inflammasome

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2013.236 ◽

2014 ◽

Vol 34 (4) ◽

pp. 621-629 ◽

Cited By ~ 132

Author(s):

Stephanie E Adamczak ◽

Juan Pablo de Rivero Vaccari ◽

Gordon Dale ◽

Frank J Brand ◽

Doris Nonner ◽

...

Keyword(s):

Cell Death ◽

Cortical Neurons ◽

Interleukin 1 ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Cns Infection ◽

Cell Death Mechanism ◽

Caspase 1 ◽

Brilliant Blue Fcf ◽

Death Effector

The central nervous system (CNS) is an active participant in the innate immune response to infection and injury. In these studies, we show embryonic cortical neurons express a functional, deoxyribonucleic acid (DNA)-responsive, absent in melanoma 2 (AIM2) inflammasome that activates caspase-1. Neurons undergo pyroptosis, a proinflammatory cell death mechanism characterized by the following: (a) oligomerization of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC); (b) caspase-1 dependency; (c) formation of discrete pores in the plasma membrane; and (d) release of the inflammatory cytokine interleukin-1 β (IL-1 β). Probenecid and Brilliant Blue FCF, inhibitors of the pannexin1 channel, prevent AIM2 inflammasome-mediated cell death, identifying pannexin1 as a cell death effector during pyroptosis and probenecid as a novel pyroptosis inhibitor. Furthermore, we show activation of the AIM2 inflammasome in neurons by cerebrospinal fluid (CSF) from traumatic brain injury (TBI) patients and oligomerization of ASC. These findings suggest neuronal pyroptosis is an important cell death mechanism during CNS infection and injury that may be attenuated by probenecid.

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