title: Snake phospholipase A2 neurotoxins enter neurons, bind specifically to mitochondria, and open their transition pores.
abstract: 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.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.
authors.forename: Michela
authors.initials: M
authors.lastname: Rigoni
authors.forename: Marco
authors.initials: M
authors.lastname: Paoli
authors.forename: Eva
authors.initials: E
authors.lastname: Milanesi
authors.forename: Paola
authors.initials: P
authors.lastname: Caccin
authors.forename: Andrea
authors.initials: A
authors.lastname: Rasola
authors.forename: Paolo
authors.initials: P
authors.lastname: Bernardi
authors.forename: Cesare
authors.initials: C
authors.lastname: Montecucco
mesh_terms: D000818:Animals; D002118:Calcium / Q000737:chemistry; D004546:Elapid Venoms / Q000737:chemistry; D005227:Fatty Acids / Q000737:chemistry; D006868:Hydrolysis; D008246:Lysophospholipids / Q000737:chemistry; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism*; D009498:Neurotoxins / Q000737:chemistry; D010539:Permeability; D054467:Phospholipases A2 / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012911:Snakes
chemical_list: D004546:Elapid Venoms; D005227:Fatty Acids; D008246:Lysophospholipids; D009498:Neurotoxins; C005082:notexin; D054467:Phospholipases A2; D002118:Calcium