Differential ROS‐Mediated Phosphorylation of Drp1 in Mitochondrial Fragmentation Induced by Distinct Cell Death Conditions in Cerebellar Granule Neurons

Cid-Castro, Carolina; Morán, Julio

doi:10.1155/2021/8832863

Cited by 12 publications

(10 citation statements)

References 96 publications

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“…CGN was treated with low potassium (5 mM) or staurosporine (0.5 μM) during 6-24 h and then neuronal viability was evaluated with calcein and propidium iodide as indicated in Methods. In line with previous studies (Valencia and Morán, 2001;Guemez-Gamboa and Morán, 2009;Ramiro-Cortés and Morán, 2009;Zaragoza-Campillo and Morán, 2017;Cid-Castro and Morán, 2021) we found a decrease in cell viability of 20% after 6 h of treatment with low potassium (K5) and by 60% after 24 h. In the case of staurosporine, we observed about 60% of cell death after 24 h of treatment. Therefore, the temporary window in which death is executed is from 18 to 24 h after the treatments (Figure 1).…”

Section: Staurosporine and Low Potassium Induce Neuronal Deathsupporting

confidence: 92%

Txnip expression promotes JNK-mediated neuronal death in response to reactive oxygen species

García-Hernández

Morán

2023

Front. Mol. Neurosci.

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TXNIP is a protein sensitive to oxidant conditions whose expression is related to the progression of death in cancer, diabetes, ischemia, and neurodegenerative diseases, among others. Because of this, many studies propose TXNIP as a therapeutic target in several diseases. Exposure of cerebellar granule neurons to staurosporine or low potassium leads to apoptotic death. Both conditions generate an early production of reactive oxygen species (ROS) that induces the activation of the ASK1 pathway and the apoptotic machinery. In these models, it has been shown an increase in TXNIP protein mediated by ROS. Here, we evaluated the molecular mechanisms involved in the regulation of the Txnip expression during neuronal death, as well as the role of the protein in the progression of cell death induced by these two apoptotic conditions. In cultured cerebellar granule neurons, we observed that low potassium and staurosporine induced an early increase in ROS that correlated with an increase in Txnip mRNA. When we evaluated the promoter of the gene, we found that the JASPAR-reported FOXO1/3 transcription factor motifs are close to the transcription start site (TSS). We then verified through the Chromatin immunoprecipitation technique (ChIP) that FOXO3 interacts with the Txnip promoter after 1 h of low potassium treatment. We also detected FOXO3 nuclear translocation by low potassium and staurosporine treatments. Finally, by using shRNA in the neuroblastoma MSN cell line, we found that Txnip downregulation decreased neuronal death induced by staurosporine stimulus. Together, these results suggest that ROS promotes the expression of Txnip through the activation of the FOXO3 transcription factor mediated by Akt inhibition. We also demonstrated that TXNIP is necessary for neuronal death progression.

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Section: Staurosporine and Low Potassium Induce Neuronal Deathsupporting

confidence: 92%

Txnip expression promotes JNK-mediated neuronal death in response to reactive oxygen species

García-Hernández

Morán

2023

Front. Mol. Neurosci.

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“…ROS are a byproduct produced during mitochondrial respiration; when mitochondrial ROS (mitoROS) levels are disturbed, interactions involving the structure and function of mitochondria may eventuate ( Forrester et al, 2018 ) and play important roles in the development of inflammatory and metabolic disorders (such as atherosclerosis and diabetes) ( Hu et al, 2020 ). Drp1 can affect mitochondrial fission by regulating the levels of mitoROS and subsequent oxidative stress ( Cid-Castro and Morán, 2021 ). In addition, ROS also regulate mitochondrial fusion.…”

Section: Novel Mechanistic Insights: From Mitochondrial Dynamics To Atherosclerosismentioning

confidence: 99%

Novel Insights and Current Evidence for Mechanisms of Atherosclerosis: Mitochondrial Dynamics as a Potential Therapeutic Target

Yang

Xing

et al. 2021

Front. Cell Dev. Biol.

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Cardiovascular disease (CVD) is the main cause of death worldwide. Atherosclerosis is the underlying pathological basis of CVD. Mitochondrial homeostasis is maintained through the dynamic processes of fusion and fission. Mitochondria are involved in many cellular processes, such as steroid biosynthesis, calcium homeostasis, immune cell activation, redox signaling, apoptosis, and inflammation, among others. Under stress conditions, mitochondrial dynamics, mitochondrial cristae remodeling, and mitochondrial ROS (mitoROS) production increase, mitochondrial membrane potential (MMP) decreases, calcium homeostasis is imbalanced, and mitochondrial permeability transition pore open (mPTP) and release of mitochondrial DNA (mtDNA) are activated. mtDNA recognized by TLR9 can lead to NF-κB pathway activation and pro-inflammatory factor expression. At the same time, TLR9 can also activate NLRP3 inflammasomes and release interleukin, an event that eventually leads to tissue damage and inflammatory responses. In addition, mitochondrial dysfunction may amplify the activation of NLRP3 through the production of mitochondrial ROS, which together aggravate accumulating mitochondrial damage. In addition, mtDNA defects or gene mutation can lead to mitochondrial oxidative stress. Finally, obesity, diabetes, hypertension and aging are risk factors for the progression of CVD, which are closely related to mitochondrial dynamics. Mitochondrial dynamics may represent a new target in the treatment of atherosclerosis. Antioxidants, mitochondrial inhibitors, and various new therapies to correct mitochondrial dysfunction represent a few directions for future research on therapeutic intervention and amelioration of atherosclerosis.

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“…Mitochondrial fission is mediated by activation of GTPase Drp1 [ 23 ]. Moreover, Drp1 activation is accompanied by an elevation of total and mitochondrial ROS (mtROS) levels [ 24 , 25 ]. Pretreatment of cells with the Drp1 inhibitor mDivi-1 at concentration of 25 μM for 1 h prevented mitochondrial fragmentation induced by Mitocur-3 but not Mitocur-1 ( Figure 4 ).…”

Section: Resultsmentioning

confidence: 99%

The Distinct Effects of the Mitochondria-Targeted STAT3 Inhibitors Mitocur-1 and Mitocur-3 on Mast Cell and Mitochondrial Functions

Pavlyuchenkova

Chelombitko

Fedorov

et al. 2023

IJMS

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There is accumulating evidence that mitochondria and mitochondrial STAT3 are involved in the activation of mast cells. The mitochondria-targeted curcuminoids Mitocur-1 and Mitocur-3 have been suggested to reduce antigen-dependent mast cell activation by inhibiting mitochondrial STAT3. The aim of the current work was to investigate the mechanisms of action of these mitocurcuminoids on mast cells and mitochondrial functions. The pretreatment of rat basophilic leukemia cells RBL-2H3 with Mitocur-1 and Mitocur-3 decreased antigen-dependent degranulation but did not affect spontaneous degranulation. Both compounds caused mitochondrial fragmentation and increased mitochondrial ROS. Inhibition of Drp1 prevented mitochondrial fragmentation induced by Mitocur-3 but not by Mitocur-1. The antioxidant N-acetylcysteine inhibited mitochondrial fission induced by Mitocur-1 but not Mitocur-3. Mitochondrial fragmentation caused by Mitocur-3 but not Mitocur-1 was accompanied by activation of Drp1 and AMPK. These data suggest a distinct mechanism of action of mitocurcuminoids on the mitochondria of RBL-2H3 cells: Mitocur-3 stimulated AMPK and caused Drp1-dependent mitochondrial fragmentation, while Mitocur-1-induced mitochondrial fission was ROS-dependent. This difference may contribute to the higher toxicity of Mitocur-3 compared to Mitocur-1. The findings contribute to further drug development for inflammatory and allergic diseases.

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Differential ROS‐Mediated Phosphorylation of Drp1 in Mitochondrial Fragmentation Induced by Distinct Cell Death Conditions in Cerebellar Granule Neurons

Cited by 12 publications

References 96 publications

Txnip expression promotes JNK-mediated neuronal death in response to reactive oxygen species

Txnip expression promotes JNK-mediated neuronal death in response to reactive oxygen species

Novel Insights and Current Evidence for Mechanisms of Atherosclerosis: Mitochondrial Dynamics as a Potential Therapeutic Target

The Distinct Effects of the Mitochondria-Targeted STAT3 Inhibitors Mitocur-1 and Mitocur-3 on Mast Cell and Mitochondrial Functions

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