Document Detail


Snake phospholipase A2 neurotoxins enter neurons, bind specifically to mitochondria, and open their transition pores.
MedLine Citation:
PMID:  18809685     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Snake presynaptic neurotoxins with phospholipase A(2) activity are potent inducers of paralysis through inhibition of the neuromuscular junction. These neurotoxins were recently shown to induce exocytosis of synaptic vesicles following the production of lysophospholipids and fatty acids and a sustained influx of Ca(2+) from the medium. Here, we show that these toxins are able to penetrate spinal cord motor neurons and cerebellar granule neurons and selectively bind to mitochondria. As a result of this interaction, mitochondria depolarize and undergo a profound shape change from elongated and spaghetti-like to round and swollen. We show that snake presynaptic phospholipase A(2) neurotoxins facilitate opening of the mitochondrial permeability transition pore, an inner membrane high-conductance channel. The relative potency of the snake neurotoxins was similar for the permeability transition pore opening and for the phospholipid hydrolysis activities, suggesting a causal relationship, which is also supported by the effect of phospholipid hydrolysis products, lysophospholipids and fatty acids, on mitochondrial pore opening. These findings contribute to define the cellular events that lead to intoxication of nerve terminals by these snake neurotoxins and suggest that mitochondrial impairment is an important determinant of their toxicity.
Authors:
Michela Rigoni; Marco Paoli; Eva Milanesi; Paola Caccin; Andrea Rasola; Paolo Bernardi; Cesare Montecucco
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-09-22
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  283     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2008 Dec 
Date Detail:
Created Date:  2008-12-01     Completed Date:  2009-02-04     Revised Date:  2013-06-05    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  34013-20     Citation Subset:  IM    
Affiliation:
Dipartimento di Scienze Biomediche Sperimentali, Università di Padova and Istituto di Neuroscienze del Consiglio Nazionale delle Ricerche, Viale Giuseppe Colombo 3, I-35121 Padova, Italy.
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MeSH Terms
Descriptor/Qualifier:
Animals
Calcium / chemistry
Elapid Venoms / chemistry
Fatty Acids / chemistry
Hydrolysis
Lysophospholipids / chemistry
Mitochondria / drug effects,  metabolism*
Models, Biological
Neurons / metabolism*
Neurotoxins / chemistry
Permeability
Phospholipases A2 / metabolism*
Rats
Rats, Wistar
Snakes
Grant Support
ID/Acronym/Agency:
GGP04113//Telethon
Chemical
Reg. No./Substance:
0/Elapid Venoms; 0/Fatty Acids; 0/Lysophospholipids; 0/Neurotoxins; 37223-96-4/notexin; 7440-70-2/Calcium; EC 3.1.1.4/Phospholipases A2
Comments/Corrections

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