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Molecular Mechanisms of Animal Toxins, Venoms and Antivenoms

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Toxicology".

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 38597

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Prof. Dr. R. Manjunatha Kini

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Guest Editor

Department of Biological Sciences, National University of Singapore, Singapore 117558, Singapore
Interests: protein chemistry; structure-function relationships; protein–protein interaction; protein design and engineering
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Yuri N. Utkin

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Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, 117997 Moscow, Russia
Interests: snake venoms; toxins; new proteins; isolation; properties; nicotinic acetylcholine receptor
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

In some animals, venoms have appeared as a means of defense and/or as a means of attack/hunting. Venoms may contain components of various chemical nature, commonly referred to as toxins. In the course of evolution, toxins have acquired the ability to selectively and effectively affect certain systems in the organism of the victim or predator. The development of methods for the identification and analysis of the chemical structure of organic compounds leads to the discovery of new toxins, for which it is necessary to establish the mechanisms of action. Moreover, new species of venomous animals are being discovered, for which it is also necessary to establish the molecular mechanisms of venom action. This understanding is very important for the effective treatment of intoxications, which still remain a serious problem in a number of regions of the planet. Currently, the most effective way to treat bites of venomous animals is the use of antisera obtained by immunizing large mammals (mainly horses) with small doses of venom. Although very effective, this method has a number of disadvantages, which requires the development of new treatments based on other molecular mechanisms. Since toxins are highly efficacious and selective for certain biological targets, they can serve as templates for drug development. Thus, the study of the molecular mechanisms of action of animal venoms, their toxins and new antitoxins is a very important task. The purpose of this Special Issue is to present the state of the art in the study of the molecular mechanisms underlying the action of animal venoms, their components and antitoxins.

Research articles, review articles as well as short communications are invited.

Please note that, for IJMS papers, theoretical studies should offer new insights into the understanding of experimental results or suggest new experimentally testable hypotheses

Prof. Dr. R. Manjunatha Kini
Prof. Dr. Yuri N. Utkin
Guest Editors

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Keywords

venom
toxin
antitoxin
antivenom
neurotoxin
cytotoxin
hemotoxin
conotoxin
snake
scorpion
spider

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Published Papers (11 papers)

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Editorial

Jump to: Research

3 pages, 199 KiB

Open AccessEditorial

Molecular Mechanisms of Animal Toxins, Venoms and Antivenoms

by R. Manjunatha Kini and Yuri N. Utkin

Int. J. Mol. Sci. 2023, 24(22), 16389; https://doi.org/10.3390/ijms242216389 - 16 Nov 2023

Cited by 1 | Viewed by 1145

Abstract

In many animals belonging to different taxa, venoms evolved as a means of defense and/or a means of attack/hunting [...] Full article

(This article belongs to the Special Issue Molecular Mechanisms of Animal Toxins, Venoms and Antivenoms)

Research

Jump to: Editorial

18 pages, 1900 KiB

Open AccessArticle

Resistance Is Not Futile: Widespread Convergent Evolution of Resistance to Alpha-Neurotoxic Snake Venoms in Caecilians (Amphibia: Gymnophiona)

by Marco Mancuso, Shabnam Zaman, Simon T. Maddock, Rachunliu G. Kamei, David Salazar-Valenzuela, Mark Wilkinson, Kim Roelants and Bryan G. Fry

Int. J. Mol. Sci. 2023, 24(14), 11353; https://doi.org/10.3390/ijms241411353 - 12 Jul 2023

Cited by 6 | Viewed by 16767

Abstract

Predatory innovations impose reciprocal selection pressures upon prey. The evolution of snake venom alpha-neurotoxins has triggered the corresponding evolution of resistance in the post-synaptic nicotinic acetylcholine receptors of prey in a complex chemical arms race. All other things being equal, animals like caecilians (an Order of legless amphibians) are quite vulnerable to predation by fossorial elapid snakes and their powerful alpha-neurotoxic venoms; thus, they are under strong selective pressure. Here, we sequenced the nicotinic acetylcholine receptor alpha-1 subunit of 37 caecilian species, representing all currently known families of caecilians from across the Americas, Africa, and Asia, including species endemic to the Seychelles. Three types of resistance were identified: (1) steric hindrance from N-glycosylated asparagines; (2) secondary structural changes due to the replacement of proline by another amino acid; and (3) electrostatic charge repulsion of the positively charged neurotoxins, through the introduction of a positively charged amino acid into the toxin-binding site. We demonstrated that resistance to alpha-neurotoxins convergently evolved at least fifteen times across the caecilian tree (three times in Africa, seven times in the Americas, and five times in Asia). Additionally, as several species were shown to possess multiple resistance modifications acting synergistically, caecilians must have undergone at least 20 separate events involving the origin of toxin resistance. On the other hand, resistance in non-caecilian amphibians was found to be limited to five origins. Together, the mutations underlying resistance in caecilians constitute a robust signature of positive selection which strongly correlates with elapid presence through both space (sympatry with caecilian-eating elapids) and time (Cenozoic radiation of elapids). Our study demonstrates the extent of convergent evolution that can be expected when a single widespread predatory adaptation triggers parallel evolutionary arms races at a global scale. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Animal Toxins, Venoms and Antivenoms)

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21 pages, 7261 KiB

Open AccessArticle

Fangs in the Ghats: Preclinical Insights into the Medical Importance of Pit Vipers from the Western Ghats

by Suyog Khochare, R. R. Senji Laxme, Priyanka Jaikumar, Navneet Kaur, Saurabh Attarde, Gerard Martin and Kartik Sunagar

Int. J. Mol. Sci. 2023, 24(11), 9516; https://doi.org/10.3390/ijms24119516 - 30 May 2023

Cited by 6 | Viewed by 3246

Abstract

The socioeconomic impact of snakebites in India is largely attributed to a subset of snake species commonly known as the ‘big four’. However, envenoming by a range of other clinically important yet neglected snakes, a.k.a. the ‘neglected many’, also adds to this burden. The current approach of treating bites from these snakes with the ‘big four’ polyvalent antivenom is ineffective. While the medical significance of various species of cobras, saw-scaled vipers, and kraits is well-established, the clinical impact of pit vipers from regions such as the Western Ghats, northeastern India, and the Andaman and Nicobar Islands remains poorly understood. Amongst the many species of snakes found in the Western Ghats, the hump-nosed (Hypnale hypnale), Malabar (Craspedocephalus malabaricus), and bamboo (Craspedocephalus gramineus) pit vipers can potentially inflict severe envenoming. To evaluate the severity of toxicity inflicted by these snakes, we characterised their venom composition, biochemical and pharmacological activities, and toxicity- and morbidity-inducing potentials, including their ability to damage kidneys. Our findings highlight the therapeutic inadequacies of the Indian and Sri Lankan polyvalent antivenoms in neutralising the local and systemic toxicity resulting from pit viper envenomings. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Animal Toxins, Venoms and Antivenoms)

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11 pages, 1673 KiB

Open AccessArticle

Effects of Cobra Cardiotoxins on Intracellular Calcium and the Contracture of Rat Cardiomyocytes Depend on Their Structural Types

by Alexey S. Averin, Alexey V. Berezhnov, Oleg Y. Pimenov, Miliausha H. Galimova, Vladislav G. Starkov, Victor I. Tsetlin and Yuri N. Utkin

Int. J. Mol. Sci. 2023, 24(11), 9259; https://doi.org/10.3390/ijms24119259 - 25 May 2023

Cited by 4 | Viewed by 1564

Abstract

Cardiotoxins (CaTx) of the three-finger toxin family are one of the main components of cobra venoms. Depending on the structure of the N-terminal or the central polypeptide loop, they are classified into either group I and II or P- and S-types, respectively, and toxins of different groups or types interact with lipid membranes variably. While their main target in the organism is the cardiovascular system, there is no data on the effects of CaTxs from different groups or types on cardiomyocytes. To evaluate these effects, a fluorescence measurement of intracellular Ca²⁺ concentration and an assessment of the rat cardiomyocytes’ shape were used. The obtained results showed that CaTxs of group I containing two adjacent proline residues in the N-terminal loop were less toxic to cardiomyocytes than group II toxins and that CaTxs of S-type were less active than P-type ones. The highest activity was observed for Naja oxiana cobra cardiotoxin 2, which is of P-type and belongs to group II. For the first time, the effects of CaTxs of different groups and types on the cardiomyocytes were studied, and the data obtained showed that the CaTx toxicity to cardiomyocytes depends on the structures both of the N-terminal and central polypeptide loops. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Animal Toxins, Venoms and Antivenoms)

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20 pages, 3716 KiB

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Inflammasome Coordinates Senescent Chronic Wound Induced by Thalassophryne nattereri Venom

by Carla Lima, Aline Ingrid Andrade-Barros, Fabiana Franco Carvalho, Maria Alice Pimentel Falcão and Monica Lopes-Ferreira

Int. J. Mol. Sci. 2023, 24(9), 8453; https://doi.org/10.3390/ijms24098453 - 8 May 2023

Viewed by 1800

Abstract

Thalassophryne nattereri toadfish (niquim) envenomation, common in the hands and feet of bathers and fishermen in the north and northeast regions of Brazil, is characterized by local symptoms such as immediate edema and intense pain. These symptoms progress to necrosis that lasts for an extended period of time, with delayed healing. Wound healing is a complex process characterized by the interdependent role of keratinocytes, fibroblasts, and endothelial and innate cells such as neutrophils and macrophages. Macrophages and neutrophils are actively recruited to clear debris during the inflammatory phase of wound repair, promoting the production of pro-inflammatory mediators, and in the late stage, macrophages promote tissue repair. Our hypothesis is that injury caused by T. nattereri venom (VTn) leads to senescent wounds. In this study, we provide valuable information about the mechanism(s) behind the dysregulated inflammation in wound healing induced by VTn. We demonstrate in mouse paws injected with the venom the installation of γH2AX/p16^Ink4a-dependent senescence with persistent neutrophilic inflammation in the proliferation and remodeling phases. VTn induced an imbalance of M1/M2 macrophages by maintaining a high number of TNF-α-producing M1 macrophages in the wound but without the ability to eliminate the persistent neutrophils. Chronic neutrophilic inflammation and senescence were mediated by cytokines such as IL-1α and IL-1β in a caspase-1- and caspase-11-dependent manner. In addition, previous blocking with anti-IL-1α and anti-IL-β neutralizing antibodies and caspase-1 (Ac YVAD-CMK) and caspase-11 (Wedelolactone) inhibitors was essential to control the pro-inflammatory activity of M1 macrophages induced by VTn injection, skewing towards an anti-inflammatory state, and was sufficient to block neutrophil recruitment and senescence. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Animal Toxins, Venoms and Antivenoms)

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18 pages, 4063 KiB

Open AccessArticle

Effective Pre-Clinical Treatment of Fish Envenoming with Polyclonal Antiserum

by Monica Lopes Ferreira, Maria Alice Pimentel Falcão, Fernanda Miriane Bruni, Vidal Haddad, Jr., Elineide Eugênio Marques, Carla Simone Seibert and Carla Lima

Int. J. Mol. Sci. 2023, 24(9), 8338; https://doi.org/10.3390/ijms24098338 - 6 May 2023

Cited by 1 | Viewed by 1818

Abstract

Envenomation by venomous fish, although not always fatal, is capable of causing damage to homeostasis by activating the inflammatory process, with the formation of edema, excruciating pain, necrosis that is difficult to heal, as well as hemodynamic and cardiorespiratory changes. Despite the wide variety of pharmacological treatments used to manage acute symptoms, none are effective in controlling envenomation. Knowing the essential role of neutralizing polyclonal antibodies in the treatment of envenoming for other species, such as snakes, this work aimed to produce a polyclonal antiserum in mice and test its ability to neutralize the main toxic effects induced by the venoms of the main venomous Brazilian fish. We found that the antiserum recognizes the main toxins present in the different venoms of Thalassophryne nattereri, Scorpaena plumieri, Potamotrygon gr. Orbignyi, and Cathorops spixii and was effective in pre-incubation trials. In an independent test, the antiserum applied immediately to the topical application of T. nattereri, P. gr orbygnyi, and C. spixii venoms completely abolished the toxic effects on the microcirculation, preventing alterations such as arteriolar contraction, slowing of blood flow in postcapillary venules, venular stasis, myofibrillar hypercontraction, and increased leukocyte rolling and adherence. The edematogenic and nociceptive activities induced by these venoms were also neutralized by the immediate application of the antiserum. Importantly, the antiserum prevented the acute inflammatory response in the lungs induced by the S. plumieri venom. The success of antiserum containing neutralizing polyclonal antibodies in controlling the toxic effects induced by different venoms offers a new strategy for the treatment of fish envenomation in Brazil. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Animal Toxins, Venoms and Antivenoms)

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11 pages, 792 KiB

Open AccessCommunication

Intracellular Zinc Trafficking during Crotalus atrox Venom Wound Development

by Eric A. Albrecht, Jasmine D. Carter, Veronica Garbar, Abeeha Choudhary and Scott A. Tomlins

Int. J. Mol. Sci. 2023, 24(7), 6763; https://doi.org/10.3390/ijms24076763 - 5 Apr 2023

Cited by 1 | Viewed by 1982

Abstract

In this study, we examined zinc trafficking in human umbilical vein endothelial cells (HUVEC) stimulated with Crotalus atrox (CA venom) snake venom. We utilized MTS cytotoxicity assays to monitor the cytotoxic range of CA venom. HUVEC monolayers stimulated with 10 µg/mL CA venom for 3 h displayed cellular retraction, which coincided with 53.0 ± 6.5 percent viability. In contrast, venom concentrations of 100 µg/mL produced a complete disruption of cellular adherence and viability decreased to 36.6 ± 1.0. The zinc probe Fluozin-3AM was used to detect intracellular zinc in non-stimulated controls, HUVEC stimulated with 10 µg/mL CA venom or HUVEC preincubated with TPEN for 2 h then stimulated with 10 µg/mL CA venom. Fluorescent intensity analysis returned values of 1434.3 ± 197.4 for CA venom demonstrating an increase of about two orders of magnitude in labile zinc compared to non-stimulated controls. Endothelial response to CA venom induced a 96.1 ± 3.0- and 4.4 ± 0.41-fold increase in metallothionein 1X (MT1X) and metallothionein 2A (MT2A) gene expression. Zinc chelation during CA venom stimulation significantly increased cell viability, suggesting that the maintenance of zinc homeostasis during envenomation injury improves cell survival. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Animal Toxins, Venoms and Antivenoms)

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18 pages, 2988 KiB

Open AccessArticle

Characterization of the First Animal Toxin Acting as an Antagonist on AT1 Receptor

by Anne-Cécile Van Baelen, Xavier Iturrioz, Marion Chaigneau, Pascal Kessler, Catherine Llorens-Cortes, Denis Servent, Nicolas Gilles and Philippe Robin

Int. J. Mol. Sci. 2023, 24(3), 2330; https://doi.org/10.3390/ijms24032330 - 24 Jan 2023

Cited by 3 | Viewed by 2578

Abstract

The renin-angiotensin system (RAS) is one of the main regulatory systems of cardiovascular homeostasis. It is mainly composed of angiotensin-converting enzyme (ACE) and angiotensin II receptors AT1 and AT2. ACE and AT1 are targets of choice for the treatment of hypertension, whereas the AT2 receptor is still not exploited due to the lack of knowledge of its physiological properties. Peptide toxins from venoms display multiple biological functions associated with varied chemical and structural properties. If Brazilian viper toxins have been described to inhibit ACE, no animal toxin is known to act on AT1/AT2 receptors. We screened a library of toxins on angiotensin II receptors with a radioligand competition binding assay. Functional characterization of the selected toxin was conducted by measuring second messenger production, G-protein activation and β-arrestin 2 recruitment using bioluminescence resonance energy transfer (BRET) based biosensors. We identified one original toxin, A-CTX-cMila, which is a 7-residues cyclic peptide from Conus miliaris with no homology sequence with known angiotensin peptides nor identified toxins, displaying a 100-fold selectivity for AT1 over AT2. This toxin shows a competitive antagonism mode of action on AT1, blocking Gαq, Gαi3, GαoA, β-arrestin 2 pathways and ERK_1/2 activation. These results describe the first animal toxin active on angiotensin II receptors. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Animal Toxins, Venoms and Antivenoms)

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20 pages, 2119 KiB

Open AccessArticle

Complement System Inhibition Modulates the Inflammation Induced by the Venom of Premolis semirufa, an Amazon Rainforest Moth Caterpillar

by Joel J. M. Gabrili, Isadora Maria Villas-Boas, Giselle Pidde, Carla Cristina Squaiella-Baptistão, Trent M. Woodruff and Denise V. Tambourgi

Int. J. Mol. Sci. 2022, 23(21), 13333; https://doi.org/10.3390/ijms232113333 - 1 Nov 2022

Cited by 3 | Viewed by 1949

Abstract

The caterpillar of the Premolis semirufa moth, commonly called Pararama, is found in the Brazilian Amazon region. Contact with the hairs can cause a chronic inflammatory reaction, termed “pararamosis”. To date, there is still no specific treatment for pararamosis. In this study, we used a whole human blood model to evaluate the involvement of the complement in the proinflammatory effects of P. semirufa hair extract, as well as the anti-inflammatory potential of complement inhibitors in this process. After treatment of blood samples with the P. semirufa hair extract, there was a significant increase in the generation of soluble terminal complement complex (sTCC) and anaphylatoxins (C3a, C4a, and C5a), as well as the production of the cytokines TNF-α and IL-17 and the chemokines IL-8, RANTES, MIG, MCP-1, and IP-10. The inhibition of C3 with compstatin significantly decreased IL-17, IL-8, RANTES, and MCP-1 production. However, the use of the C5aR1 antagonist PMX205 promoted a reduction in the production of IL-8 and RANTES. Moreover, compstatin decreased CD11b, C5aR1, and TLR2 expression induced by P. semirufa hair extract in granulocytes and CD11b, TLR4, and TLR2 in monocytes. When we incubated vascular endothelial cells with extract-treated human plasma, there was an increase in IL-8 and MCP-1 production, and compstatin was able to decrease the production of these chemokines. C5aR1 antagonism also decreased the production of MCP-1 in endothelial cells. Thus, these results indicate that the extract of the Pararama bristles activates the complement system and that this action contributes to the production of cytokines and chemokines, modulation of the expression of surface markers in leukocytes, and activation of endothelial cells. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Animal Toxins, Venoms and Antivenoms)

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17 pages, 2988 KiB

Open AccessArticle

The Deadly Toxin Arsenal of the Tree-Dwelling Australian Funnel-Web Spiders

by Fernanda C. Cardoso, Sandy S. Pineda, Volker Herzig, Kartik Sunagar, Naeem Yusuf Shaikh, Ai-Hua Jin, Glenn F. King, Paul F. Alewood, Richard J. Lewis and Sébastien Dutertre

Int. J. Mol. Sci. 2022, 23(21), 13077; https://doi.org/10.3390/ijms232113077 - 28 Oct 2022

Cited by 5 | Viewed by 2951

Abstract

Australian funnel-web spiders are amongst the most dangerous venomous animals. Their venoms induce potentially deadly symptoms, including hyper- and hypotension, tachycardia, bradycardia and pulmonary oedema. Human envenomation is more frequent with the ground-dwelling species, including the infamous Sydney funnel-web spider (Atrax robustus); although, only two tree-dwelling species induce more severe envenomation. To unravel the mechanisms that lead to this stark difference in clinical outcomes, we investigated the venom transcriptome and proteome of arboreal Hadronyche cerberea and H. formidabilis. Overall, Hadronyche venoms comprised 44 toxin superfamilies, with 12 being exclusive to tree-dwellers. Surprisingly, the major venom components were neprilysins and uncharacterized peptides, in addition to the well-known ω- and δ-hexatoxins and double-knot peptides. The insecticidal effects of Hadronyche venom on sheep blowflies were more potent than Atrax venom, and the venom of both tree- and ground-dwelling species potently modulated human voltage-gated sodium channels, particularly Na_V1.2. Only the venom of tree-dwellers exhibited potent modulation of voltage-gated calcium channels. H. formidabilis appeared to be under less diversifying selection pressure compared to the newly adapted tree-dweller, H. cerberea. Thus, this study contributes to unravelling the fascinating molecular and pharmacological basis for the severe envenomation caused by the Australian tree-dwelling funnel-web spiders. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Animal Toxins, Venoms and Antivenoms)

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15 pages, 4358 KiB

Open AccessArticle

Rat Group IIA Secreted Phospholipase A₂ Binds to Cytochrome c Oxidase and Inhibits Its Activity: A Possible Episode in the Development of Alzheimer’s Disease

by Adrijan Ivanušec, Jernej Šribar, Adrijana Leonardi, Maja Zorović, Marko Živin and Igor Križaj

Int. J. Mol. Sci. 2022, 23(20), 12368; https://doi.org/10.3390/ijms232012368 - 15 Oct 2022

Cited by 4 | Viewed by 1895

Abstract

Alzheimer’s disease (AD), a progressive form of dementia, is characterized by the increased expression of secreted phospholipase A₂ group IIA (GIIA) in the affected tissue and the dysfunction of neuronal mitochondria, similar to that induced by an orthologous GIIA from snake venom, β-neurotoxic ammodytoxin (Atx), in the motor neurons. To advance our knowledge about the role of GIIA in AD, we studied the effect of rat GIIA on the neuronal mitochondria and compared it with that of the Atx. We produced recombinant rat GIIA (rGIIA) and its enzymatically inactive mutant, rGIIA(D49S), and demonstrated that they interact with the subunit II of cytochrome c oxidase (CCOX-II) as Atx. rGIIA and rGIIA(D49S) bound to this essential constituent of the respiratory chain complex with an approximately 100-fold lower affinity than Atx; nevertheless, both rGIIA molecules potently inhibited the CCOX activity in the isolated rat mitochondria. Like Atx, rGIIA was able to reach the mitochondria in the PC12 cells from the extracellular space, independent of its enzymatic activity. Consistently, the inhibition of the CCOX activity in the intact PC12 cells and in the rat’s brain tissue sections was clearly demonstrated using rGIIA(D49S). Our results show that the effects of mammalian and snake venom β-neurotoxic GIIA on the neuronal mitochondria have similar molecular backgrounds. They suggest that the elevated extracellular concentration of GIIA in the AD tissue drives the translocation of this enzyme into local neurons and their mitochondria to inhibit the activity of the CCOX in the respiratory chain. Consequently, the process of oxidative phosphorylation in the neurons is attenuated, eventually leading to their degeneration. Atx was thus revealed as a valuable molecular tool for further investigations of the role of GIIA in AD. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Animal Toxins, Venoms and Antivenoms)

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