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Naja mossambica mossambica Cobra Cardiotoxin Targets Mitochondria to Disrupt Mitochondrial Membrane Structure and Function.

ABSTRACT: Cobra venom cardiotoxins (CVCs) can translocate to mitochondria to promote apoptosis by eliciting mitochondrial dysfunction. However, the molecular mechanism(s) by which CVCs are selectively targeted to the mitochondrion to disrupt mitochondrial function remains to be elucidated. By studying cardiotoxin from Naja mossambica mossambica cobra (cardiotoxin VII4), a basic three-fingered S-type cardiotoxin, we hypothesized that cardiotoxin VII4 binds to cardiolipin (CL) in mitochondria to alter mitochondrial structure/function and promote neurotoxicity. By performing confocal analysis, we observed that red-fluorescently tagged cardiotoxin rapidly translocates to mitochondria in mouse primary cortical neurons and in human SH-SY5Y neuroblastoma cells to promote aberrant mitochondrial fragmentation, a decline in oxidative phosphorylation, and decreased energy production. In addition, by employing electron paramagnetic resonance (EPR) and protein nuclear magnetic resonance (¹H-NMR) spectroscopy and phosphorescence quenching of erythrosine in model membranes, our compiled biophysical data show that cardiotoxin VII4 binds to anionic CL, but not to zwitterionic phosphatidylcholine (PC), to increase the permeability and formation of non-bilayer structures in CL-enriched membranes that biochemically mimic the outer and inner mitochondrial membranes. Finally, molecular dynamics simulations and in silico docking studies identified CL binding sites in cardiotoxin VII4 and revealed a molecular mechanism by which cardiotoxin VII4 interacts with CL and PC to bind and penetrate mitochondrial membranes.

SUBMITTER: Zhang B

PROVIDER: S-EPMC6468758 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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<i>Naja mossambica mossambica</i> Cobra Cardiotoxin Targets Mitochondria to Disrupt Mitochondrial Membrane Structure and Function.

Zhang Boris B Li Feng F Chen Zhengyao Z Shrivastava Indira H IH Gasanoff Edward S ES Dagda Ruben K RK

Toxins 20190308 3

Cobra venom cardiotoxins (CVCs) can translocate to mitochondria to promote apoptosis by eliciting mitochondrial dysfunction. However, the molecular mechanism(s) by which CVCs are selectively targeted to the mitochondrion to disrupt mitochondrial function remains to be elucidated. By studying cardiotoxin from <i>Naja mossambica mossambica</i> cobra (cardiotoxin VII4), a basic three-fingered S-type cardiotoxin, we hypothesized that cardiotoxin VII4 binds to cardiolipin (CL) in mitochondria to alte ...[more]

PMID: 30857180

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Project description:Objectives:The objective of the present work was to examine the bacterial flora associated with the oral cavity of Indian cobra and to study their antibiogram. Methods:Oral swabs, collected from six healthy (4 males and 2 females) adult cobra, were subjected to microbiological examination through differential media. A total of 74 isolates which demonstrated noticeable colony characters were studied with different biochemical tests. The strains that showed distinctive colonies, morphology and biochemical parameters were additionally subjected to phylogenetic characterization using 16S rRNA gene sequences. Further, the isolates were subjected to antimicrobial susceptibility testing using ICOSA-20-plus and ICOSA-20-minus. Results:Microscopic examination of the oral cavity of Indian cobra revealed the dominance of Gram-negative bacteria over Gram-positive. The oral microflora constituted of bacteria such as Salmonella sp. (S. typhi, S. paratyphi A); Pseudomonas sp. (P. aeruginosa, P. fluorescence); Proteus sp. (P. mirabilis, P. penneri, P. vulgaris); E. coli; Morganella sp.; Citrobacter sp. (C. diversus, C. freundii); Aeromonas sp. (A. hydrophila, A. salmonicida); Enterobacter sp. (E. aerogens); Acinetobacter sp. (A. baumannii); Neisseria sp.; Serratia sp.; Bacillus sp. (B. cereus, B. megatarium, B. atrophaeus and B. weihenstephanensis); Enterococcus sp. (E. faecalis, E. faecium); Staphylococcus sp. (S. aureus, S. epidermidis); Alcaligenes sp.; Chryseobacterium sp. and Micrococcus sp. Most of the isolates were resistant towards antibiotics such as Penicillin, Cefpodoxime, Amoxyclav, Co-Trimoxazole, Ticarcillin, Erythromycin and Nalidixic acid while sensitive towards Ciprofloxacin, Gentamicin, Ofloxacin, Sparfloxacin, Tobromycin, Ceftriaxone, Tetracycline, Novobiocin and Imipenem. Conclusions:The secondary complications of the snake bite victims should be managed with appropriate antibiotics after proper examination of the bacterial flora from the wound sites.

Project description:BackgroundIntraspecific variations in snake venom composition have been extensively documented, contributing to the diverse clinical effects observed in envenomed patients. Understanding these variations is essential for developing effective snakebite management strategies and targeted antivenom therapies. We aimed to comprehensively investigate venoms from three distinct populations of N. mossambica from Eswatini, Limpopo, and KwaZulu-Natal regions in Africa in terms of their protein composition and reactivity with three commercial antivenoms (SAIMR polyvalent, EchiTAb+ICP, and Antivipmyn Africa).Methodology/principal findingsNaja mossambica venoms from Eswatini region exhibited the highest content of neurotoxic proteins, constituting 20.70% of all venom proteins, compared to Limpopo (13.91%) and KwaZulu-Natal (12.80%), and was characterized by the highest diversity of neurotoxic proteins, including neurotoxic 3FTxs, Kunitz-type inhibitors, vespryns, and mamba intestinal toxin 1. KwaZulu-Natal population exhibited considerably lower cytotoxic 3FTx, higher PLA2 content, and significant diversity in low-abundant proteins. Conversely, Limpopo venoms demonstrated the least diversity as demonstrated by electrophoretic and mass spectrometry analyses. Immunochemical assessments unveiled differences in venom-antivenom reactivity, particularly concerning low-abundance proteins. EchiTAb+ICP antivenom demonstrated superior reactivity in serial dilution ELISA assays compared to SAIMR polyvalent.Conclusions/significanceOur findings reveal a substantial presence of neurotoxic proteins in N. mossambica venoms, challenging previous understandings of their composition. Additionally, the detection of numerous peptides aligning to uncharacterized proteins or proteins with unknown functions underscores a critical issue with existing venom protein databases, emphasizing the substantial gaps in our knowledge of snake venom protein components. This underscores the need for enhanced research in this domain. Moreover, our in vitro immunological assays suggest EchiTAb+ICP's potential as an alternative to SAIMR antivenom, requiring confirmation through prospective in vivo neutralization studies.

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Naja mossambica mossambica Cobra Cardiotoxin Targets Mitochondria to Disrupt Mitochondrial Membrane Structure and Function.

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<i>Naja mossambica mossambica</i> Cobra Cardiotoxin Targets Mitochondria to Disrupt Mitochondrial Membrane Structure and Function.

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