scholarly journals Identification of Elongation Factor-2 as a Novel Regulator of Mitochondrial Fission

2021 ◽  
Author(s):  
Jinhwan Kim ◽  
Yan Cheng ◽  
Yanfeng Li ◽  
Yi Zhang ◽  
Ji Cheng ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Critical Role ◽  
Elongation Factor ◽  
Binding Motif ◽  
Gtpase Activity ◽  
Elongation Factor 2 ◽  
Gtp Binding ◽  
And Function

Abstract Mitochondria continuously undergo morphologically dynamic processes of fusion and fission to maintain their size, shape, amount, and function; yet the precise molecular mechanisms by which mitochondrial dynamics is regulated remain to be fully elucidated. Here, we report a previous unappreciated but critical role of eukaryotic elongation factor 2 (eEF2) in regulating mitochondrial fission. eEF2, a G-protein superfamily member encoded by EEF2 gene in human, has long been appreciated as a promoter of the GTP-dependent translocation of the ribosome during protein synthesis. We found unexpectedly in several types of cells that eEF2 was not only present in the cytosol but also in the mitochondria. Furthermore, we showed that mitochondrial length was significantly increased when the cells were subjected to silencing of eEF2 expression, suggesting a promotive role for eEF2 in the mitochondrial fission. Inversely, overexpression of eEF2 decreased mitochondrial length, suggesting an increase of mitochondrial fission. Inhibition of mitochondrial fission caused by eEF2 depletion was accompanied by alterations of cellular metabolism, as evidenced by a reduction of oxygen consumption and an increase of oxidative stress in the mitochondria. We further demonstrated that eEF2 and Drp1, a key driver of mitochondrial fission, co-localized at the mitochondria, as evidenced by microscopic observation, co-immunoprecipitation, and GST pulldown assay. Deletion of the GTP binding motif of eEF2 decreased its association with Drp1 and abrogated its effect on mitochondria fission. Moreover, we showed that wild-type eEF2 stimulated GTPase activity of Drp1, whereas deletion of the GTP binding site of eEF2 diminished its stimulatory effect on GTPase activity. This work not only reveals a previously unrecognized function of eEF2 (i.e., promoting mitochondrial fission), but also uncovers the interaction of eEF2 with Drp1 as a novel regulatory mechanism of the mitochondrial dynamics. Therefore, eEF2 warrants further exploration for its potential as a therapeutic target for the mitochondria-related diseases.

scholarly journals Methamphetamine induces cardiomyopathy by Sigmar1 inhibition-dependent impairment of mitochondrial dynamics and function

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Chowdhury S. Abdullah ◽  
Richa Aishwarya ◽  
Shafiul Alam ◽  
Mahboob Morshed ◽  
Naznin Sultana Remex ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Therapeutic Agent ◽  
Illicit Drug ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Camp Response Element Binding ◽  
Camp Response Element ◽  
Element Binding Protein ◽  
Dynamics And Function ◽  
And Function

AbstractMethamphetamine-associated cardiomyopathy is the leading cause of death linked with illicit drug use. Here we show that Sigmar1 is a therapeutic target for methamphetamine-associated cardiomyopathy and defined the molecular mechanisms using autopsy samples of human hearts, and a mouse model of “binge and crash” methamphetamine administration. Sigmar1 expression is significantly decreased in the hearts of human methamphetamine users and those of “binge and crash” methamphetamine-treated mice. The hearts of methamphetamine users also show signs of cardiomyopathy, including cellular injury, fibrosis, and enlargement of the heart. In addition, mice expose to “binge and crash” methamphetamine develop cardiac hypertrophy, fibrotic remodeling, and mitochondrial dysfunction leading to contractile dysfunction. Methamphetamine treatment inhibits Sigmar1, resulting in inactivation of the cAMP response element-binding protein (CREB), decreased expression of mitochondrial fission 1 protein (FIS1), and ultimately alteration of mitochondrial dynamics and function. Therefore, Sigmar1 is a viable therapeutic agent for protection against methamphetamine-associated cardiomyopathy.

scholarly journals Mechanosensation and Mechanotransduction by Lymphatic Endothelial Cells Act as Important Regulators of Lymphatic Development and Function

2021 ◽  
Vol 22 (8) ◽  
pp. 3955
Author(s):  
László Bálint ◽  
Zoltán Jakus
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Mechanical Forces ◽  
Lymphatic Endothelial Cells ◽  
Lymphatic Development ◽  
And Function ◽  
The Impact

Our understanding of the function and development of the lymphatic system is expanding rapidly due to the identification of specific molecular markers and the availability of novel genetic approaches. In connection, it has been demonstrated that mechanical forces contribute to the endothelial cell fate commitment and play a critical role in influencing lymphatic endothelial cell shape and alignment by promoting sprouting, development, maturation of the lymphatic network, and coordinating lymphatic valve morphogenesis and the stabilization of lymphatic valves. However, the mechanosignaling and mechanotransduction pathways involved in these processes are poorly understood. Here, we provide an overview of the impact of mechanical forces on lymphatics and summarize the current understanding of the molecular mechanisms involved in the mechanosensation and mechanotransduction by lymphatic endothelial cells. We also discuss how these mechanosensitive pathways affect endothelial cell fate and regulate lymphatic development and function. A better understanding of these mechanisms may provide a deeper insight into the pathophysiology of various diseases associated with impaired lymphatic function, such as lymphedema and may eventually lead to the discovery of novel therapeutic targets for these conditions.

scholarly journals Expression and function of Smad7 in autoimmune and inflammatory diseases

2021 ◽  
Author(s):  
Yiping Hu ◽  
Juan He ◽  
Lianhua He ◽  
Bihua Xu ◽  
Qingwen Wang
Keyword(s):  
Posttranscriptional Regulation ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Inflammatory Diseases ◽  
Kidney Diseases ◽  
Critical Role ◽  
Transforming Growth Factor Β ◽  
Negative Regulator ◽  
Signaling Mechanism ◽  
And Function

AbstractTransforming growth factor-β (TGF-β) plays a critical role in the pathological processes of various diseases. However, the signaling mechanism of TGF-β in the pathological response remains largely unclear. In this review, we discuss advances in research of Smad7, a member of the I-Smads family and a negative regulator of TGF-β signaling, and mainly review the expression and its function in diseases. Smad7 inhibits the activation of the NF-κB and TGF-β signaling pathways and plays a pivotal role in the prevention and treatment of various diseases. Specifically, Smad7 can not only attenuate growth inhibition, fibrosis, apoptosis, inflammation, and inflammatory T cell differentiation, but also promotes epithelial cells migration or disease development. In this review, we aim to summarize the various biological functions of Smad7 in autoimmune diseases, inflammatory diseases, cancers, and kidney diseases, focusing on the molecular mechanisms of the transcriptional and posttranscriptional regulation of Smad7.

scholarly journals Mitochondrial Dynamics Regulation in Skin Fibroblasts from Mitochondrial Disease Patients

Biomolecules ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 450 ◽  
Author(s):  
Takeshi Tokuyama ◽  
Asei Hirai ◽  
Isshin Shiiba ◽  
Naoki Ito ◽  
Keigo Matsuno ◽  
...  
Keyword(s):  
Mitochondrial Disease ◽  
Mitochondrial Myopathy ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Critical Role ◽  
Leigh Syndrome ◽  
Mitochondrial Morphology ◽  
Mitochondrial Fragmentation ◽  
Cellular Toxicity ◽  
Morphologic Changes

Mitochondria are highly dynamic organelles that constantly fuse, divide, and move, and their function is regulated and maintained by their morphologic changes. Mitochondrial disease (MD) comprises a group of disorders involving mitochondrial dysfunction. However, it is not clear whether changes in mitochondrial morphology are related to MD. In this study, we examined mitochondrial morphology in fibroblasts from patients with MD (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and Leigh syndrome). We observed that MD fibroblasts exhibited significant mitochondrial fragmentation by upregulation of Drp1, which is responsible for mitochondrial fission. Interestingly, the inhibition of mitochondrial fragmentation by Drp1 knockdown enhanced cellular toxicity and led to cell death in MD fibroblasts. These results suggest that mitochondrial fission plays a critical role in the attenuation of mitochondrial damage in MD fibroblasts.

scholarly journals A Novel mTOR-Regulated Phosphorylation Site in Elongation Factor 2 Kinase Modulates the Activity of the Kinase and Its Binding to Calmodulin

2004 ◽  
Vol 24 (7) ◽  
pp. 2986-2997 ◽  
Author(s):  
Gareth J. Browne ◽  
Christopher G. Proud
Keyword(s):  
Amino Acids ◽  
Protein Kinase ◽  
Phosphorylation Site ◽  
Elongation Factor ◽  
Mtor Pathway ◽  
Mtor Signaling ◽  
Chain Elongation ◽  
Binding Motif ◽  
Elongation Factor 2 ◽  
Eef2 Kinase

ABSTRACT Eukaryotic elongation factor 2 (eEF2) kinase is an unusual calcium- and calmodulin-dependent protein kinase that is regulated by insulin through the rapamycin-sensitive mTOR pathway. Here we show that insulin decreases the ability of eEF2 kinase to bind calmodulin in a rapamycin-sensitive manner. We identify a novel phosphorylation site in eEF2 kinase (Ser78) that is located immediately next to its calmodulin-binding motif. Phosphorylation of this site is increased by insulin in a rapamycin-sensitive fashion. Regulation of the phosphorylation of Ser78 also requires amino acids and the protein kinase phosphoinositide-dependent kinase 1. Mutation of this site to alanine strongly attenuates the effects of insulin and rapamycin both on the binding of calmodulin to eEF2 kinase and on eEF2 kinase activity. Phosphorylation of Ser78 is thus likely to link insulin and mTOR signaling to the control of eEF2 phosphorylation and chain elongation. This site is not a target for known kinases in the mTOR pathway, e.g., the S6 kinases, implying that it is phosphorylated by a novel mTOR-linked protein kinase that serves to couple hormones and amino acids to the control of translation elongation. eEF2 kinase is thus a target for mTOR signaling independently of previously known downstream components of the pathway.

Astrocyte-neuron crosstalk through Hedgehog signaling mediates cortical circuit assembly

2020 ◽  
Author(s):  
Yajun Xie ◽  
Aaron T. Kuan ◽  
Wengang Wang ◽  
Zachary T. Herbert ◽  
Olivia Mosto ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Molecular Mechanisms ◽  
Synapse Formation ◽  
Critical Role ◽  
Shh Signaling ◽  
Shh Pathway ◽  
Cortical Astrocytes ◽  
Functional Features ◽  
And Function ◽  
Circuit Assembly

SUMMARYNeuron-glia relationships play a critical role in the regulation of synapse formation and neuronal specification. The cellular and molecular mechanisms by which neurons and astrocytes communicate and coordinate are not well understood. Here we demonstrate that the canonical Sonic hedgehog (Shh) pathway is active in cortical astrocytes, where it acts to coordinate layer-specific synaptic connectivity and functional circuit development. We show that Ptch1 is a Shh receptor that is expressed by cortical astrocytes during development and that Shh signaling is necessary and sufficient to promote the expression of layer-specific astrocyte genes involved in regulating synapse formation and function. Loss of Shh in layer V neurons reduces astrocyte complexity and coverage by astrocytic processes in tripartite synapses, moreover, cell-autonomous activation of Shh signaling in astrocytes promotes cortical excitatory synapse formation. Together, these results suggest that Shh secreted from deep layer cortical neurons acts to specialize the molecular and functional features of astrocytes during development to shape circuit assembly and function.

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 PPARγExpression and Function in Mycobacterial Infection: Roles in Lipid Metabolism, Immunity, and Bacterial Killing

PPAR Research ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Patricia E. Almeida ◽  
Alan Brito Carneiro ◽  
Adriana R. Silva ◽  
Patricia T. Bozza
Keyword(s):  
Molecular Mechanisms ◽  
Critical Role ◽  
Mycobacterial Infection ◽  
Receptor Activation ◽  
Host Cells ◽  
Current Evidence ◽  
Peroxisome Proliferator ◽  
Bacterial Killing ◽  
Peroxisome Proliferator Activated Receptor ◽  
And Function

Tuberculosis continues to be a global health threat, with drug resistance and HIV coinfection presenting challenges for its control.Mycobacterium tuberculosis, the etiological agent of tuberculosis, is a highly adapted pathogen that has evolved different strategies to subvert the immune and metabolic responses of host cells. Although the significance of peroxisome proliferator-activated receptor gamma (PPARγ) activation by mycobacteria is not fully understood, recent findings are beginning to uncover a critical role for PPARγduring mycobacterial infection. Here, we will review the molecular mechanisms that regulate PPARγexpression and function during mycobacterial infection. Current evidence indicates that mycobacterial infection causes a time-dependent increase in PPARγexpression through mechanisms that involve pattern recognition receptor activation. Mycobacterial triggered increased PPARγexpression and activation lead to increased lipid droplet formation and downmodulation of macrophage response, suggesting that PPARγexpression might aid the mycobacteria in circumventing the host response acting as an escape mechanism. Indeed, inhibition of PPARγenhances mycobacterial killing capacity of macrophages, suggesting a role of PPARγin favoring the establishment of chronic infection. Collectively, PPARγis emerging as a regulator of tuberculosis pathogenesis and an attractive target for the development of adjunctive tuberculosis therapies.

scholarly journals The mode of action of Shiga toxin on peptide elongation of eukaryotic protein synthesis

1987 ◽  
Vol 244 (2) ◽  
pp. 287-294 ◽  
Author(s):  
T G Obrig ◽  
T P Moran ◽  
J E Brown
Keyword(s):  
Protein Synthesis ◽  
Complex Formation ◽  
Shiga Toxin ◽  
Mode Of Action ◽  
Elongation Factor ◽  
Shigella Dysenteriae ◽  
Gtpase Activity ◽  
Elongation Factor 2 ◽  
Peptide Elongation ◽  
Elongation Factor 1

The effect of Shiga toxin, from Shigella dysenteriae 1, on the component reactions of peptide elongation were investigated. Enzymic binding of [3H]phenylalanine-tRNA to reticulocyte ribosomes was inhibited by 50% at 7 nM toxin. Elongation factor 1 (eEF-1)-dependent GTPase activity was also inhibited. Both reactions were not restored by addition of excess eEF-1 protein. In contrast, toxin concentrations of 200 nM were required to inhibit by 50% the elongation factor 2 (eEF-2)-dependent translocation of aminoacyl-tRNA on ribosomes. Addition of excess eEF-2 restored translocation activity. The eEF-2-dependent GTPase activity was unaffected at toxin concentrations below 100 nM, and Shiga-toxin concentrations of up to 1,000 nM did not affect either GTP.eEF-2.ribosome complex-formation or peptidyltransferase activity. Thus Shiga toxin closely resembles alpha-sarcin in action, both being primary inhibitors of eEF-1-dependent reactions. In contrast, the 60 S ribosome inactivators ricin and phytolaccin are primary inhibitors of eEF-2-dependent reactions of peptide elongation.

scholarly journals The Mitochondrial Fission Regulator DRP1 Controls Post-Transcriptional Regulation of TNF-α

2021 ◽  
Vol 10 ◽  
Author(s):  
Fushan Gao ◽  
Mack B. Reynolds ◽  
Karla D. Passalacqua ◽  
Jonathan Z. Sexton ◽  
Basel H. Abuaita ◽  
...  
Keyword(s):  
Transcriptional Control ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Critical Role ◽  
Innate Immune ◽  
Sterile Inflammation ◽  
Proinflammatory Response ◽  
Immune Signaling ◽  
Innate Immune Signaling ◽  
Tnf Α

The mitochondrial network plays a critical role in the regulation of innate immune signaling and subsequent production of proinflammatory cytokines such as IFN-β and IL-1β. Dynamin-related protein 1 (DRP1) promotes mitochondrial fission and quality control to maintain cellular homeostasis during infection. However, mechanisms by which DRP1 and mitochondrial dynamics control innate immune signaling and the proinflammatory response are incompletely understood. Here we show that macrophage DRP1 is a positive regulator of TNF-α production during sterile inflammation or bacterial infection. Silencing macrophage DRP1 decreased mitochondrial fragmentation and TNF-α production upon stimulation with lipopolysaccharide (LPS) or methicillin-resistant Staphylococcus aureus (MRSA) infection. The defect in TNF-α induction could not be attributed to changes in gene expression. Instead, DRP1 was required for post-transcriptional control of TNF-α. In contrast, silencing DRP1 enhanced IL-6 and IL-1β production, indicating a distinct mechanism for DRP1-dependent TNF-α regulation. Our results highlight DRP1 as a key player in the macrophage pro-inflammatory response and point to its involvement in post-transcriptional control of TNF-α production.

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