Molecular Mechanisms of Calcium Influx in Axonal Degeneration

Lithium has emerged as a neuroprotective agent efficacious in preventing apoptosis-dependent cellular death. Lithium neuroprotection is provided through multiple, intersecting mechanisms, although how lithium interacts with these mechanisms is still under investigation. Lithium increases cell survival by inducing brain-derived neurotrophic factor and thereby stimulating activity in anti-apoptotic pathways, including the phosphatidylinositol 3-kinase/Akt and the mitogen-activated protein kinase pathways. In addition, lithium reduces pro-apoptotic function by directly and indirectly inhibiting glycogen synthase kinase-3β activity and indirectly inhibiting N-methyl-D-aspartate (NMDA)-receptor-mediated calcium influx. Lithium-induced regulation of anti- and pro-apoptotic pathways alters a wide variety of downstream effectors, including β-catenin, heat shock factor 1, activator protein 1, cAMP-response-element-binding protein, and the Bcl-2 protein family. Lithium neuroprotection has a wide variety of clinical implications. Beyond its present use in bipolar mood disorder, lithium's neuroprotective abilities imply that it could be used to treat or prevent brain damage following traumatic injury, such as stroke, and neurodegenerative diseases such as Huntington's and Alzheimer's diseases.

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DDIT3 (CHOP) contributes to retinal ganglion cell somal loss but not axonal degeneration in DBA/2J mice

Cell Death Discovery ◽

10.1038/s41420-019-0220-4 ◽

2019 ◽

Vol 5 (1) ◽

Cited By ~ 5

Author(s):

Olivia J. Marola ◽

Stephanie B. Syc-Mazurek ◽

Richard T. Libby

Keyword(s):

Optic Nerve ◽

Ocular Hypertension ◽

Optic Nerve Head ◽

Cellular Response ◽

Molecular Mechanisms ◽

Axonal Degeneration ◽

Axonal Injury ◽

Retinal Ganglion ◽

Age Related

Abstract Glaucoma is an age-related neurodegenerative disease characterized by the progressive loss of retinal ganglion cells (RGCs). Chronic ocular hypertension, an important risk factor for glaucoma, leads to RGC axonal injury at the optic nerve head. This insult triggers molecularly distinct cascades governing RGC somal apoptosis and axonal degeneration. The molecular mechanisms activated by ocular hypertensive insult that drive both RGC somal apoptosis and axonal degeneration are incompletely understood. The cellular response to endoplasmic reticulum stress and induction of pro-apoptotic DNA damage inducible transcript 3 (DDIT3, also known as CHOP) have been implicated as drivers of neurodegeneration in many disease models, including glaucoma. RGCs express DDIT3 after glaucoma-relevant insults, and importantly, DDIT3 has been shown to contribute to both RGC somal apoptosis and axonal degeneration after acute induction of ocular hypertension. However, the role of DDIT3 in RGC somal and axonal degeneration has not been critically tested in a model of age-related chronic ocular hypertension. Here, we investigated the role of DDIT3 in glaucomatous RGC death using an age-related, naturally occurring ocular hypertensive mouse model of glaucoma, DBA/2J mice (D2). To accomplish this, a null allele of Ddit3 was backcrossed onto the D2 background. Homozygous Ddit3 deletion did not alter gross retinal or optic nerve head morphology, nor did it change the ocular hypertensive profile of D2 mice. In D2 mice, Ddit3 deletion conferred mild protection to RGC somas, but did not significantly prevent RGC axonal degeneration. Together, these data suggest that DDIT3 plays a minor role in perpetuating RGC somal apoptosis caused by chronic ocular hypertension-induced axonal injury, but does not significantly contribute to distal axonal degeneration.

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The role of mitochondria in axonal degeneration and tissue repair in MS

Multiple Sclerosis Journal ◽

10.1177/1352458512452924 ◽

2012 ◽

Vol 18 (8) ◽

pp. 1058-1067 ◽

Cited By ~ 43

Author(s):

J van Horssen ◽

ME Witte ◽

O Ciccarelli

Keyword(s):

Mitochondrial Dysfunction ◽

Tissue Repair ◽

Molecular Mechanisms ◽

Axonal Degeneration ◽

Axonal Damage ◽

Mitochondrial Metabolism ◽

Imaging Studies ◽

And Function

Axonal injury is a key feature of multiple sclerosis (MS) pathology and is currently seen as the main correlate for permanent clinical disability. Although little is known about the pathogenetic mechanisms that drive axonal damage and loss, there is accumulating evidence highlighting the central role of mitochondrial dysfunction in axonal degeneration and associated neurodegeneration. The aim of this topical review is to provide a concise overview on the involvement of mitochondrial dysfunction in axonal damage and destruction in MS. Hereto, we will discuss putative pathological mechanisms leading to mitochondrial dysfunction and recent imaging studies performed in vivo in patients with MS. Moreover, we will focus on molecular mechanisms and novel imaging studies that address the role of mitochondrial metabolism in tissue repair. Finally, we will briefly review therapeutic strategies aimed at improving mitochondrial metabolism and function under neuroinflammatory conditions.

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MCTP is an ER-resident calcium sensor that stabilizes synaptic transmission and homeostatic plasticity

eLife ◽

10.7554/elife.22904 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 21

Author(s):

Özgür Genç ◽

Dion K Dickman ◽

Wenpei Ma ◽

Amy Tong ◽

Richard D Fetter ◽

...

Keyword(s):

Synaptic Transmission ◽

Molecular Mechanisms ◽

Calcium Influx ◽

Homeostatic Plasticity ◽

Calcium Sensor ◽

C2 Domains ◽

Calcium Dependent ◽

Disease Associations ◽

Transmembrane Regions ◽

Presynaptic Calcium

Presynaptic homeostatic plasticity (PHP) controls synaptic transmission in organisms from Drosophila to human and is hypothesized to be relevant to the cause of human disease. However, the underlying molecular mechanisms of PHP are just emerging and direct disease associations remain obscure. In a forward genetic screen for mutations that block PHP we identified mctp (Multiple C2 Domain Proteins with Two Transmembrane Regions). Here we show that MCTP localizes to the membranes of the endoplasmic reticulum (ER) that elaborate throughout the soma, dendrites, axon and presynaptic terminal. Then, we demonstrate that MCTP functions downstream of presynaptic calcium influx with separable activities to stabilize baseline transmission, short-term release dynamics and PHP. Notably, PHP specifically requires the calcium coordinating residues in each of the three C2 domains of MCTP. Thus, we propose MCTP as a novel, ER-localized calcium sensor and a source of calcium-dependent feedback for the homeostatic stabilization of neurotransmission.

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Sensory cilia as the Achilles heel of nematodes when attacked by carnivorous mushrooms

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1918473117 ◽

2020 ◽

Vol 117 (11) ◽

pp. 6014-6022 ◽

Cited By ~ 1

Author(s):

Ching-Han Lee ◽

Han-Wen Chang ◽

Ching-Ting Yang ◽

Niaz Wali ◽

Jiun-Jie Shie ◽

...

Keyword(s):

Molecular Mechanisms ◽

Calcium Influx ◽

Muscle Cells ◽

Nematode Species ◽

Predatory Behavior ◽

Parasitic Nematodes ◽

Loss Of Function ◽

Genetic Screens ◽

Predator Prey ◽

C Elegans

Fungal predatory behavior on nematodes has evolved independently in all major fungal lineages. The basidiomycete oyster mushroomPleurotus ostreatusis a carnivorous fungus that preys on nematodes to supplement its nitrogen intake under nutrient-limiting conditions. Its hyphae can paralyze nematodes within a few minutes of contact, but the mechanism had remained unclear. We demonstrate that the predator–prey relationship is highly conserved between multiplePleurotusspecies and a diversity of nematodes. To further investigate the cellular and molecular mechanisms underlying rapid nematode paralysis, we conducted genetic screens inCaenorhabditis elegansand isolated mutants that became resistant toP. ostreatus. We found that paralysis-resistant mutants all harbored loss-of-function mutations in genes required for ciliogenesis, demonstrating that the fungus induced paralysis via the cilia of nematode sensory neurons. Furthermore, we observed thatP. ostreatuscaused excess calcium influx and hypercontraction of the head and pharyngeal muscle cells, ultimately resulting in rapid necrosis of the entire nervous system and muscle cells throughout the entire organism. This cilia-dependent predatory mechanism is evolutionarily conserved inPristionchus pacificus, a nematode species estimated to have diverged fromC. elegans280 to 430 million y ago. Thus,P. ostreatusexploits a nematode-killing mechanism that is distinct from widely used anthelmintic drugs such as ivermectin, levamisole, and aldicarb, representing a potential route for targeting parasitic nematodes in plants, animals, and humans.

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Dissecting Cellular Mechanisms of Long-Chain Acylcarnitines-Driven Cardiotoxicity: Disturbance of Calcium Homeostasis, Activation of Ca2+-Dependent Phospholipases, and Mitochondrial Energetics Collapse

International Journal of Molecular Sciences ◽

10.3390/ijms21207461 ◽

2020 ◽

Vol 21 (20) ◽

pp. 7461

Author(s):

Alexey V. Berezhnov ◽

Evgeniya I. Fedotova ◽

Miroslav N. Nenov ◽

Vitaly A. Kasymov ◽

Oleg Yu. Pimenov ◽

...

Keyword(s):

Molecular Mechanisms ◽

Mitochondrial Permeability Transition ◽

Calcium Influx ◽

Ischemia Reperfusion ◽

Fluorescent Microscopy ◽

Complex Nature ◽

Dependent Manner ◽

Cellular Mechanisms ◽

Mitochondrial Potential ◽

Long Chain

Long-chain acylcarnitines (LCAC) are implicated in ischemia-reperfusion (I/R)-induced myocardial injury and mitochondrial dysfunction. Yet, molecular mechanisms underlying involvement of LCAC in cardiac injury are not sufficiently studied. It is known that in cardiomyocytes, palmitoylcarnitine (PC) can induce cytosolic Ca2+ accumulation, implicating L-type calcium channels, Na+/Ca2+ exchanger, and Ca2+-release from sarcoplasmic reticulum (SR). Alternatively, PC can evoke dissipation of mitochondrial potential (ΔΨm) and mitochondrial permeability transition pore (mPTP). Here, to dissect the complex nature of PC action on Ca2+ homeostasis and oxidative phosphorylation (OXPHOS) in cardiomyocytes and mitochondria, the methods of fluorescent microscopy, perforated path-clamp, and mitochondrial assays were used. We found that LCAC in dose-dependent manner can evoke Ca2+-sparks and oscillations, long-living Ca2+ enriched microdomains, and, finally, Ca2+ overload leading to hypercontracture and cardiomyocyte death. Collectively, PC-driven cardiotoxicity involves: (I) redistribution of Ca2+ from SR to mitochondria with minimal contribution of external calcium influx; (II) irreversible inhibition of Krebs cycle and OXPHOS underlying limited mitochondrial Ca2+ buffering; (III) induction of mPTP reinforced by PC-calcium interplay; (IV) activation of Ca2+-dependent phospholipases cPLA2 and PLC. Based on the inhibitory analysis we may suggest that simultaneous inhibition of both phospholipases could be an effective strategy for protection against PC-mediated toxicity in cardiomyocytes.

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Alterations of GABAergic Signaling in Autism Spectrum Disorders

Neural Plasticity ◽

10.1155/2011/297153 ◽

2011 ◽

Vol 2011 ◽

pp. 1-12 ◽

Cited By ~ 145

Author(s):

Rocco Pizzarelli ◽

Enrico Cherubini

Keyword(s):

Autism Spectrum Disorders ◽

Molecular Mechanisms ◽

Synapse Formation ◽

Calcium Influx ◽

Adult Life ◽

Stereotyped Behavior ◽

Autism Spectrum ◽

Neuronal Circuits ◽

Inhibitory Neurotransmitter ◽

Spectrum Disorders

Autism spectrum disorders (ASDs) comprise a heterogeneous group of pathological conditions, mainly of genetic origin, characterized by stereotyped behavior, marked impairment in verbal and nonverbal communication, social skills, and cognition. Interestingly, in a small number of cases, ASDs are associated with single mutations in genes encoding for neuroligin-neurexin families. These are adhesion molecules which, by regulating transsynaptic signaling, contribute to maintain a proper excitatory/inhibitory (E/I) balance at the network level. Furthermore, GABA, the main inhibitory neurotransmitter in adult life, at late embryonic/early postnatal stages has been shown to depolarize and excite targeted cell through an outwardly directed flux of chloride. The depolarizing action of GABA and associated calcium influx regulate a variety of developmental processes from cell migration and differentiation to synapse formation. Here, we summarize recent data concerning the functional role of GABA in building up and refining neuronal circuits early in development and the molecular mechanisms regulating the E/I balance. A dysfunction of the GABAergic signaling early in development leads to a severe E/I unbalance in neuronal circuits, a condition that may account for some of the behavioral deficits observed in ASD patients.

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The Src homology 2 domain–containing inositol 5-phosphatase negatively regulates Fcγ receptor–mediated phagocytosis through immunoreceptor tyrosine-based activation motif–bearing phagocytic receptors

Blood ◽

10.1182/blood-2002-03-0787 ◽

2002 ◽

Vol 100 (9) ◽

pp. 3374-3382 ◽

Cited By ~ 66

Author(s):

Koji Nakamura ◽

Alexander Malykhin ◽

K. Mark Coggeshall

Keyword(s):

B Cells ◽

Molecular Mechanisms ◽

Calcium Influx ◽

Dominant Negative ◽

Src Homology 2 ◽

Dominant Negative Form ◽

Igg Receptors ◽

Src Homology ◽

Src Homology 2 Domain ◽

Activation Motif

Abstract Molecular mechanisms by which the Src homology 2 domain-containing inositol 5-phosphatase (SHIP) negatively regulates phagocytosis in macrophages are unclear. We addressed the issue using bone marrow–derived macrophages from FcγR- or SHIP-deficient mice. Phagocytic activities of macrophages from FcγRII(b)−/− and SHIP−/− mice were enhanced to a similar extent, relative to those from wild type. However, calcium influx was only marginally affected in FcγRII(b)−/−, but greatly enhanced in SHIP−/− macrophages. Furthermore, SHIP was phosphorylated on tyrosine residues upon FcγR aggregation even in macrophages from FcγRII(b)−/− mice or upon clustering of a chimeric receptor containing CD8 and the immunoreceptor tyrosine-based activation motif (ITAM)–bearing γ-chain or human-restricted FcγRIIa. These findings indicate that, unlike B cells, SHIP is efficiently phosphorylated in the absence of an immunoreceptor tyrosine-based inhibition motif (ITIM)–bearing receptor. We further demonstrate that SHIP directly bound to phosphorylated peptides derived from FcγRIIa with a high affinity, comparable to that of FcγRII(b). Lastly, FcγRIIa-mediated phagocytosis was significantly enhanced in THP-1 cells overexpressing dominant-negative form of SHIP in the absence of FcγRII(b). These results indicate that SHIP negatively regulates FcγR-mediated phagocytosis through all ITAM-containing IgG receptors using a molecular mechanism distinct from that in B cells.

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Mitochondrial dynamics: overview of molecular mechanisms

Essays in Biochemistry ◽

10.1042/ebc20170104 ◽

2018 ◽

Vol 62 (3) ◽

pp. 341-360 ◽

Cited By ~ 197

Author(s):

Lisa Tilokani ◽

Shun Nagashima ◽

Vincent Paupe ◽

Julien Prudent

Keyword(s):

Membrane Fusion ◽

Mitochondrial Membrane ◽

Molecular Mechanisms ◽

Calcium Influx ◽

Mitochondrial Dynamics ◽

Mitochondrial Fission ◽

Membrane Lipid ◽

Inner Mitochondrial Membrane ◽

Step Process ◽

Shape Distribution

Mitochondria are highly dynamic organelles undergoing coordinated cycles of fission and fusion, referred as ‘mitochondrial dynamics’, in order to maintain their shape, distribution and size. Their transient and rapid morphological adaptations are crucial for many cellular processes such as cell cycle, immunity, apoptosis and mitochondrial quality control. Mutations in the core machinery components and defects in mitochondrial dynamics have been associated with numerous human diseases. These dynamic transitions are mainly ensured by large GTPases belonging to the Dynamin family. Mitochondrial fission is a multi-step process allowing the division of one mitochondrion in two daughter mitochondria. It is regulated by the recruitment of the GTPase Dynamin-related protein 1 (Drp1) by adaptors at actin- and endoplasmic reticulum-mediated mitochondrial constriction sites. Drp1 oligomerization followed by mitochondrial constriction leads to the recruitment of Dynamin 2 to terminate membrane scission. Inner mitochondrial membrane constriction has been proposed to be an independent process regulated by calcium influx. Mitochondrial fusion is driven by a two-step process with the outer mitochondrial membrane fusion mediated by mitofusins 1 and 2 followed by inner membrane fusion, mediated by optic atrophy 1. In addition to the role of membrane lipid composition, several members of the machinery can undergo post-translational modifications modulating these processes. Understanding the molecular mechanisms controlling mitochondrial dynamics is crucial to decipher how mitochondrial shape meets the function and to increase the knowledge on the molecular basis of diseases associated with morphology defects. This article will describe an overview of the molecular mechanisms that govern mitochondrial fission and fusion in mammals.

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Post-Translational Modifications in NETosis and NETs-Mediated Diseases

Biomolecules ◽

10.3390/biom9080369 ◽

2019 ◽

Vol 9 (8) ◽

pp. 369 ◽

Cited By ~ 10

Author(s):

Hamam ◽

Palaniyar

Keyword(s):

Histone Acetylation ◽

Cancer Progression ◽

Lupus Erythematosus ◽

Molecular Mechanisms ◽

Calcium Influx ◽

Critical Role ◽

Control Cell ◽

Clear Understanding ◽

Post Translational Modifications ◽

Histone Citrullination

: Neutrophils undergo a unique form of cell death that generates neutrophil extracellular traps (NETs) that may help to neutralize invading pathogens and restore homeostasis. However, uncontrolled NET formation (NETosis) can result in numerous diseases that adversely affect health. Recent studies further elucidate the mechanistic details of the different forms of NETosis and their common end structure, as NETs were constantly found to contain DNA, modified histones and cytotoxic enzymes. In fact, emerging evidence reveal that the post translational modifications (PTMs) of histones in neutrophils have a critical role in regulating neutrophil death. Histone citrullination is shown to promote a rapid form of NET formation independent of NADPH oxidase (NOX), which relies on calcium influx. Interestingly, few studies suggest an association between histone citrullination and other types of PTMs to control cell survival and death, such as histone methylation. Even more exciting is the finding that histone acetylation has a biphasic effect upon NETosis, where histone deacetylase (HDAC) inhibitors promote baseline, NOX-dependent and -independent NETosis. However, increasing levels of histone acetylation suppresses NETosis, and to switch neutrophil death to apoptosis. Interestingly, in the presence of NETosis-promoting stimuli, high levels of HDACis limit both NETosis and apoptosis, and promote neutrophil survival. Recent studies also reveal the importance of the PTMs of neutrophils in influencing numerous pathologies. Histone modifications in NETs can act as a double-edged sword, as they are capable of altering multiple types of neutrophil death, and influencing numerous NET-mediated diseases, such as acute lung injury (ALI), thrombosis, sepsis, systemic lupus erythematosus, and cancer progression. A clear understanding of the role of different PTMs in neutrophils would be important for an understanding of the molecular mechanisms of NETosis, and to appropriately treat NETs-mediated diseases.

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