scholarly journals CDDO-Me Selectively Attenuates CA1 Neuronal Death Induced by Status Epilepticus via Facilitating Mitochondrial Fission Independent of LONP1

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 833 ◽  
Author(s):  
Kim ◽  
Park ◽  
Choi ◽  
Kong ◽  
Kang
Keyword(s):  
Status Epilepticus ◽  
Neuronal Death ◽  
Granule Cells ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Acid Methyl Ester ◽  
Underlying Mechanism ◽  
Ca1 Neurons ◽  
Prolonged Seizure ◽  
Mitochondrial Elongation

2-Cyano-3,12-dioxo-oleana-1,9(11)-dien-28-oic acid methyl ester (CDDO-Me) is a triterpenoid analogue of oleanolic acid that exhibits promising anti-cancer, anti-inflammatory, antioxidant and neuroprotective activities. In addition, CDDO-Me affects cellular differentiation and cell cycle arrest, and irreversibly inhibits Lon protease-1 (LONP1). In the present study, we evaluate the effects of CDDO-Me on mitochondrial dynamics and its downstream effectors in order to understand the underlying mechanism of the neuronal death following status epilepticus (SE, a prolonged seizure activity). CDDO-Me increased dynamin-related proteins 1 (DRP1)-serine 616 phosphorylation via activating extracellular-signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK), but not protein kinase A (PKA) or protein phosphatases (PPs). In addition, CDDO-Me facilitated DRP1-mediated mitochondrial fissions, which selectively attenuated SE-induced CA1 neuronal death. Unlike CDDO-Me, LONP1 knockdown led to SE-induced massive degeneration of dentate granule cells, CA1 neurons and hilus interneurons without altering the expression and phosphorylation of DRP1, ERK1/2, JNK and PP2B. LONP1 knockdown could not inhibit SE-induced mitochondrial elongation in CA1 neurons. Co-treatment of CDDO-Me with LONP1 siRNA ameliorated only CA1 neuronal death, concomitant with abrogation of mitochondrial elongation induced by SE. Thus, our findings suggest that CDDO-Me may selectively attenuate SE-induced CA1 neuronal death by rescuing the abnormal mitochondrial machinery, independent of LONP1 activity.

scholarly journals TRPC6-Mediated ERK1/2 Activation Increases Dentate Granule Cell Resistance to Status Epilepticus Via Regulating Lon Protease-1 Expression and Mitochondrial Dynamics

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1376 ◽  
Author(s):  
Kim ◽  
Park ◽  
Choi ◽  
Kong ◽  
Kang
Keyword(s):  
Status Epilepticus ◽  
Granule Cell ◽  
Molecular Mechanisms ◽  
Transient Receptor Potential ◽  
Mitochondrial Dynamics ◽  
Neurological Diseases ◽  
Mitochondrial Fission ◽  
Receptor Potential ◽  
Lon Protease ◽  
Dentate Granule Cell

Transient receptor potential canonical channel-6 (TRPC6) is one of the Ca2+-permeable non-selective cation channels. TRPC6 is mainly expressed in dentate granule cell (DGC), which is one of the most resistant neuronal populations to various harmful stresses. Although TRPC6 knockdown evokes the massive DGC degeneration induced by status epilepticus (a prolonged seizure activity, SE), the molecular mechanisms underlying the role of TRPC6 in DGC viability in response to SE are still unclear. In the present study, hyperforin (a TRPC6 activator) facilitated mitochondrial fission in DGC concomitant with increases in Lon protease-1 (LONP1, a mitochondrial protease) expression and extracellular-signal-regulated kinase 1/2 (ERK1/2) phosphorylation under physiological conditions, which were abrogated by U0126 (an ERK1/2 inhibitor) co-treatment. TRPC6 knockdown showed the opposite effects on LONP1 expression, ERK1/2 activity, and mitochondrial dynamics. In addition, TRPC6 siRNA and U0126 evoked the massive DGC degeneration accompanied by mitochondrial elongation following SE, independent of seizure severity. However, LONP1 siRNA exacerbated SE-induced DGC death without affecting mitochondrial length. These findings indicate that TRPC6-ERK1/2 activation may increase DGC invulnerability to SE by regulating LONP1 expression as well as mitochondrial dynamics. Therefore, TRPC6-ERK1/2-LONP1 signaling pathway will be an interesting and important therapeutic target for neuroprotection from various neurological diseases.

scholarly journals Aorta-on-a-chip reveals impaired mitochondrial dynamics as a therapeutic target for aortic aneurysm in bicuspid aortic valve disease

2021 ◽  
Author(s):  
Abudupataer Mieradilijiang ◽  
Shichao Zhu ◽  
Shiqiang Yan ◽  
Kehua Xu ◽  
Jingjing Zhang ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Aortic Aneurysm ◽  
Bicuspid Aortic Valve ◽  
Therapeutic Target ◽  
Mitochondrial Dynamics ◽  
Science And Technology ◽  
Mitochondrial Fission ◽  
Underlying Mechanism ◽  
Mitochondrial Fusion ◽  
Contractile Phenotype

Background: Bicuspid aortic valve (BAV) is the most common congenital cardiovascular disease in general population and is frequently associated with the development of thoracic aortic aneurysm (TAA). There is no effective strategy to intervene with TAA progression due to an incomplete understanding of the pathogenesis. Insufficiency of NOTCH1 expression is highly related to BAV-TAA, but the underlying mechanism remains to be clarified. <br />Methods: A comparative proteomics analysis was used to explore the biological differences between non-diseased and BAV-TAA aortic tissues. A microfluidics-based aorta-on-a-chip model was constructed to evaluate the effect of NOTCH1 deficiency on contractile phenotype and mitochondrial dynamics of human aortic smooth muscle cells (HAoSMCs). <br />Results: Protein analyses of human aortic tissues showed the insufficient expression of NOTCH1 and impaired mitochondrial dynamics in BAV-TAA. HAoSMCs with NOTCH1-knockdown exhibited reduced contractile phenotype and were accompanied by attenuated mitochondrial fusion. Furthermore, we identified that mitochondrial fusion activators (leflunomide and teriflunomide) or mitochondrial fission inhibitor (Mdivi-1) partially rescued the disorders of mitochondrial dynamics in HAoSMCs derived from BAV-TAA patients. <br />Conclusions: The aorta-on-a-chip model simulates the human pathophysiological parameters of aorta biomechanics and provides a platform for molecular mechanism studies of aortic disease and related drug screening. This aorta-on-a-chip model and human tissue proteomic analysis revealed that impaired mitochondrial dynamics could be a potential therapeutic target for BAV-TAA. <br /><br />Funding: National Key R&D Program of China, National Natural Science Foundation of China, Shanghai Municipal Science and Technology Major Project, Shanghai Science and Technology Commission, and Shanghai Municipal Education Commission.

scholarly journals SNARE-dependent mitochondria-lysosome contacts regulate glial mitochondrial dynamics and dopaminergic neuron survival

2021 ◽  
Author(s):  
Honglei Wang ◽  
Linfang Wang ◽  
Shuanglong Yi ◽  
Shiping Zhang ◽  
Margaret Ho
Keyword(s):  
Dopaminergic Neuron ◽  
Lipid Droplets ◽  
Structural Modification ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Snare Proteins ◽  
Spatial Cues ◽  
Present Evidence ◽  
Neuron Survival ◽  
Mitochondrial Elongation

Mitochondria are dynamic organelles that undergo fission and fusion, enabling swift structural modification to adapt cellular needs. Disturbances in mitochondrial dynamics, frequently defects ascribed to neurons, have been associated with pathological contexts such as neurodegeneration in Parkinson's disease. Nonetheless, the mechanism of glial mitochondrial dynamics contributing to neurodegeneration remains unclear. Here we present evidence that the Drosophila R-SNARE VAMP7 regulates glial mitochondrial dynamics and dopaminergic neuron survival via modulating the dynamic of mitochondria-lysosome contact, which determines the mitochondrial fission site. Independent of its characterized role in autophagosome-lysosome fusion, glial VAMP7 depletion causes mitochondrial elongation and dysfunction, increased ROS levels, and production of lipid droplets. These conferred changes in glia in turn affects nearby dopaminergic neuron survival. Glial VAMP7 genetically interacts with the mitochondrial fission/fusion factors Drp1 and Marf1 and controls glial mitochondrial dynamics via regulating the frequency and duration of mitochondria-lysosome contact. Our findings indicate that SNARE proteins, although not direct mediators on mitochondrial fusion, provide spatial cues to modulate glial mitochondrial fission via organelle contacts, impacting on neuron survival in a non-cell-autonomous manner.

scholarly journals The COVID-19 Effect on the Immune System and Mitochondrial Dynamics in Diabetes, Obesity, and Dementia

2020 ◽  
pp. 107385842096044 ◽  
Author(s):  
Katherine Holder ◽  
P. Hemachandra Reddy
Keyword(s):  
Viral Replication ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Respiratory Illness ◽  
Host Cells ◽  
Age Related ◽  
Infected Cells ◽  
Current Article ◽  
Obesity Hypertension ◽  
Mitochondrial Elongation

The coronavirus disease 2019 (COVID-19) is a pandemic disease, originated in Wuhan City, China. It is caused by severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) and its biology is still poorly understood. Currently, there are no vaccines and drugs/or agents that can reduce severity of this new disease. Recent data suggest that patients with age-related comorbidities, including cardiovascular disease, diabetes, obesity, hypertension, chronic kidney disease, and dementia are highly susceptible to severe respiratory illness due to coronavirus infection. Recent research also revealed that aged individuals with elevated baseline inflammation cause defects in T and B cells, leading to decreased body’s immune response to viral infection. In the current article, we discuss the effects of SARS-CoV-2 on age-related chronic diseases, such as diabetes, obesity, and Alzheimer’s disease. Our article also highlights the interaction between coronavirus and immune cells, and how COVID-19 alters mitochondrial activities in host cells. Based on new and compelling evidence, we propose that mitochondrial fission is inhibited while fusion is promoted, causing mitochondrial elongation and providing a receptive intracellular environment for viral replication in infected cells. Further research is still needed to understand the cross talk between viral replication in mitochondria and disease progression in patients with COVID-19.

scholarly journals Fis1, Mff, MiD49, and MiD51 mediate Drp1 recruitment in mitochondrial fission

2013 ◽  
Vol 24 (5) ◽  
pp. 659-667 ◽  
Author(s):  
Oliver C. Losón ◽  
Zhiyin Song ◽  
Hsiuchen Chen ◽  
David C. Chan
Keyword(s):  
Membrane Proteins ◽  
Outer Membrane ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Outer Membrane Proteins ◽  
Mitochondrial Outer Membrane ◽  
Related Protein ◽  
Immunofluorescence Analysis ◽  
Multiple Receptors ◽  
Mitochondrial Elongation

Several mitochondrial outer membrane proteins—mitochondrial fission protein 1 (Fis1), mitochondrial fission factor (Mff), mitochondrial dynamics proteins of 49 and 51 kDa (MiD49 and MiD51, respectively)—have been proposed to promote mitochondrial fission by recruiting the GTPase dynamin-related protein 1 (Drp1), but fundamental issues remain concerning their function. A recent study supported such a role for Mff but not for Fis1. In addition, it is unclear whether MiD49 and MiD51 activate or inhibit fission, because their overexpression causes extensive mitochondrial elongation. It is also unknown whether these proteins can act in the absence of one another to mediate fission. Using Fis1-null, Mff-null, and Fis1/Mff-null cells, we show that both Fis1 and Mff have roles in mitochondrial fission. Moreover, immunofluorescence analysis of Drp1 suggests that Fis1 and Mff are important for the number and size of Drp1 puncta on mitochondria. Finally, we find that either MiD49 or MiD51 can mediate Drp1 recruitment and mitochondrial fission in the absence of Fis1 and Mff. These results demonstrate that multiple receptors can recruit Drp1 to mediate mitochondrial fission.

scholarly journals Mitochondrial fission and mitophagy are independent mechanisms regulating ischemia/reperfusion injury in primary neurons

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Anthony R. Anzell ◽  
Garrett M. Fogo ◽  
Zoya Gurm ◽  
Sarita Raghunayakula ◽  
Joseph M. Wider ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Ischemia Reperfusion Injury ◽  
Mitochondrial Dynamics ◽  
Ischemia Reperfusion ◽  
Mitochondrial Fission ◽  
Conditional Knockout ◽  
Mitochondrial Morphology ◽  
Primary Neurons ◽  
Mitochondrial Fragmentation

AbstractMitochondrial dynamics and mitophagy are constitutive and complex systems that ensure a healthy mitochondrial network through the segregation and subsequent degradation of damaged mitochondria. Disruption of these systems can lead to mitochondrial dysfunction and has been established as a central mechanism of ischemia/reperfusion (I/R) injury. Emerging evidence suggests that mitochondrial dynamics and mitophagy are integrated systems; however, the role of this relationship in the context of I/R injury remains unclear. To investigate this concept, we utilized primary cortical neurons isolated from the novel dual-reporter mitochondrial quality control knockin mice (C57BL/6-Gt(ROSA)26Sortm1(CAG-mCherry/GFP)Ganl/J) with conditional knockout (KO) of Drp1 to investigate changes in mitochondrial dynamics and mitophagic flux during in vitro I/R injury. Mitochondrial dynamics was quantitatively measured in an unbiased manner using a machine learning mitochondrial morphology classification system, which consisted of four different classifications: network, unbranched, swollen, and punctate. Evaluation of mitochondrial morphology and mitophagic flux in primary neurons exposed to oxygen-glucose deprivation (OGD) and reoxygenation (OGD/R) revealed extensive mitochondrial fragmentation and swelling, together with a significant upregulation in mitophagic flux. Furthermore, the primary morphology of mitochondria undergoing mitophagy was classified as punctate. Colocalization using immunofluorescence as well as western blot analysis revealed that the PINK1/Parkin pathway of mitophagy was activated following OGD/R. Conditional KO of Drp1 prevented mitochondrial fragmentation and swelling following OGD/R but did not alter mitophagic flux. These data provide novel evidence that Drp1 plays a causal role in the progression of I/R injury, but mitophagy does not require Drp1-mediated mitochondrial fission.

scholarly journals Syntaxin-17-Dependent Mitochondrial Dynamics is Essential for Protection Against Oxidative-Stress-Induced Apoptosis

Antioxidants ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 522 ◽  
Author(s):  
Wang ◽  
Xiao ◽  
Huang ◽  
Liu
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Autophagic Flux ◽  
Wild Type ◽  
Dual Roles ◽  
Defective Mutant ◽  
U2os Cells ◽  
Induced Apoptosis

In this study, cell death induced by the oxidant tert-butylhydroperoxide (tBH) was observed in U2OS cells; this phenotype was rescued by Syntaxin 17 (STX17) knockout (KO) but the mechanism is unknown. STX17 plays dual roles in autophagosome–lysosome fusion and mitochondrial fission. However, the contribution of the two functions of STX17 to apoptosis has not been extensively studied. Here, we sought to dissect the dual roles of STX17 in oxidative-stress-induced apoptosis by taking advantage of STX17 knockout cells and an autophagosome–lysosome fusion defective mutant of STX17. We generated STX17 knockout U2OS cells using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system and the STX17 knockout cells were reconstituted with wild-type STX17 and its autophagosome–lysosome fusion defective mutant. Autophagy was assessed by autophagic flux assay, Monomer red fluorescent protein (mRFP)–GFP–LC3 assay and protease protection assay. Golgi, endoplasmic reticulum (ER)/ER–Golgi intermediate compartment (ERGIC) and mitochondrial dynamics were examined by staining the different indicator proteins. Apoptosis was evaluated by caspase cleavage assay. The general reactive oxygen species (ROS) were detected by flow cytometry. In STX17 complete knockout cells, sealed autophagosomes were efficiently formed but their fusion with lysosomes was less defective. The fusion defect was rescued by wild-type STX17 but not the autophagosome–lysosome fusion defective mutant. No obvious defects in Golgi, ERGIC or ER dynamics were observed. Mitochondria were significantly elongated, supporting a role of STX17 in mitochondria fission and the elongation caused by STX17 KO was reversed by the autophagosome–lysosome fusion defective mutant. The clearance of protein aggregation was compromised, correlating with the autophagy defect but not with mitochondrial dynamics. This study revealed a mixed role of STX17 in autophagy, mitochondrial dynamics and oxidative stress response. STX17 knockout cells were highly resistant to oxidative stress, largely due to the function of STX17 in mitochondrial fission rather than autophagy.

scholarly journals Non-alcoholic fatty liver disease in mice with hepatocyte-specific deletion of mitochondrial fission factor

Diabetologia ◽  
2021 ◽  
Author(s):  
Yukina Takeichi ◽  
Takashi Miyazawa ◽  
Shohei Sakamoto ◽  
Yuki Hanada ◽  
Lixiang Wang ◽  
...  
Keyword(s):  
Er Stress ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Primary Hepatocytes ◽  
Alcoholic Fatty Liver ◽  
Expression Of Genes ◽  
Specific Deletion

Abstract Aims/hypothesis Mitochondria are highly dynamic organelles continuously undergoing fission and fusion, referred to as mitochondrial dynamics, to adapt to nutritional demands. Evidence suggests that impaired mitochondrial dynamics leads to metabolic abnormalities such as non-alcoholic steatohepatitis (NASH) phenotypes. However, how mitochondrial dynamics are involved in the development of NASH is poorly understood. This study aimed to elucidate the role of mitochondrial fission factor (MFF) in the development of NASH. Methods We created mice with hepatocyte-specific deletion of MFF (MffLiKO). MffLiKO mice fed normal chow diet (NCD) or high-fat diet (HFD) were evaluated for metabolic variables and their livers were examined by histological analysis. To elucidate the mechanism of development of NASH, we examined the expression of genes related to endoplasmic reticulum (ER) stress and lipid metabolism, and the secretion of triacylglycerol (TG) using the liver and primary hepatocytes isolated from MffLiKO and control mice. Results MffLiKO mice showed aberrant mitochondrial morphologies with no obvious NASH phenotypes during NCD, while they developed full-blown NASH phenotypes in response to HFD. Expression of genes related to ER stress was markedly upregulated in the liver from MffLiKO mice. In addition, expression of genes related to hepatic TG secretion was downregulated, with reduced hepatic TG secretion in MffLiKO mice in vivo and in primary cultures of MFF-deficient hepatocytes in vitro. Furthermore, thapsigargin-induced ER stress suppressed TG secretion in primary hepatocytes isolated from control mice. Conclusions/interpretation We demonstrated that ablation of MFF in liver provoked ER stress and reduced hepatic TG secretion in vivo and in vitro. Moreover, MffLiKO mice were more susceptible to HFD-induced NASH phenotype than control mice, partly because of ER stress-induced apoptosis of hepatocytes and suppression of TG secretion from hepatocytes. This study provides evidence for the role of mitochondrial fission in the development of NASH. Graphical abstract

A De Novo Dominant Negative Mutation in DNM1L Causes Sudden Onset Status Epilepticus with Subsequent Epileptic Encephalopathy

2019 ◽  
Vol 50 (03) ◽  
pp. 197-201
Author(s):  
S. Schmid ◽  
M. Wagner ◽  
C. Goetz ◽  
C. Makowski ◽  
P. Freisinger ◽  
...  
Keyword(s):  
Status Epilepticus ◽  
Missense Mutation ◽  
De Novo ◽  
Mitochondrial Fission ◽  
Refractory Status Epilepticus ◽  
Sudden Onset ◽  
Epileptic Encephalopathy ◽  
Neurologic Outcome ◽  
Dominant Negative Mutation ◽  
Refractory Status

AbstractMitochondrial dynamics such as fission and fusion play a vital role in normal brain development and neuronal activity. DNM1L encodes a dynamin-related protein 1 (Drp1), which is a GTPase essential for proper mitochondrial fission. The clinical phenotype of DNM1L mutations depends on the degree of mitochondrial fission deficiency, ranging from severe encephalopathy and death shortly after birth to initially normal development and then sudden onset of refractory status epilepticus with very poor neurologic outcome. We describe a case of a previously healthy 3-year-old boy with a mild delay in speech development until the acute onset of a refractory status epilepticus with subsequent epileptic encephalopathy and very poor neurologic outcome. The de novo missense mutation in DNM1L (c.1207C > T, p.R403C), which we identified in this case, seems to determine a unique clinical course, strikingly similar to four previously described patients in literature with the identical de novo heterozygous missense mutation in DNM1L.

scholarly journals CDDO-Me Distinctly Regulates Regional Specific Astroglial Responses to Status Epilepticus via ERK1/2-Nrf2, PTEN-PI3K-AKT and NFκB Signaling Pathways

Antioxidants ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 1026
Author(s):  
Ji-Eun Kim ◽  
Hana Park ◽  
Tae-Cheon Kang
Keyword(s):  
Status Epilepticus ◽  
Signaling Pathways ◽  
Seizure Activity ◽  
Molecular Layer ◽  
Antioxidant Properties ◽  
Acid Methyl Ester ◽  
Related Factor ◽  
Nuclear Factor ◽  
Reactive Astrogliosis ◽  
Nrf2 Expression

2-Cyano-3,12-dioxo-oleana-1,9(11)-dien-28-oic acid methyl ester (CDDO-Me) is a triterpenoid analogue of oleanolic acid. CDDO-Me shows anti-inflammatory and neuroprotective effects. Furthermore, CDDO-Me has antioxidant properties, since it activates nuclear factor-erythroid 2-related factor 2 (Nrf2), which is a key player of redox homeostasis. In the present study, we evaluated whether CDDO-Me affects astroglial responses to status epilepticus (SE, a prolonged seizure activity) in the rat hippocampus in order to understand the underlying mechanisms of reactive astrogliosis and astroglial apoptosis. Under physiological conditions, CDDO-Me increased Nrf2 expression in the hippocampus without altering activities (phosphorylations) of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), phosphatidylinositol-3-kinase (PI3K), and AKT. CDDO-Me did not affect seizure activity in response to pilocarpine. However, CDDO-Me ameliorated reduced astroglial Nrf2 expression in the CA1 region and the molecular layer of the dentate gyrus (ML), and attenuated reactive astrogliosis and ML astroglial apoptosis following SE. In CA1 astrocytes, CDDO-Me inhibited the PI3K/AKT pathway by activating PTEN. In contrast, CDDO-ME resulted in extracellular signal-related kinases 1/2 (ERK1/2)-mediated Nrf2 upregulation in ML astrocytes. Furthermore, CDDO-Me decreased nuclear factor-κB (NFκB) phosphorylation in both CA1 and ML astrocytes. Therefore, our findings suggest that CDDO-Me may attenuate SE-induced reactive astrogliosis and astroglial apoptosis via regulation of ERK1/2-Nrf2, PTEN-PI3K-AKT, and NFκB signaling pathways.

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