Rigoni Michela, Paoli Marco, Milanesi Eva, Caccin Paola, Rasola Andrea, Bernardi Paolo, Montecucco Cesare
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.
J Biol Chem. 2008 Dec 5;283(49):34013-20. doi: 10.1074/jbc.M803243200. Epub 2008 Sep 22.
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.
具有磷脂酶A(2)活性的蛇类突触前神经毒素是通过抑制神经肌肉接头而导致麻痹的强效诱导剂。最近研究表明，这些神经毒素在产生溶血磷脂和脂肪酸以及Ca(2+)从培养基中持续内流后，会诱导突触小泡的胞吐作用。在此，我们证明这些毒素能够穿透脊髓运动神经元和小脑颗粒神经元，并选择性地与线粒体结合。这种相互作用的结果是，线粒体去极化并经历从细长的意大利面条状到圆形和肿胀的深刻形态变化。我们表明，蛇类突触前磷脂酶A(2)神经毒素促进线粒体通透性转换孔（一种内膜高电导通道）的开放。蛇类神经毒素在通透性转换孔开放和磷脂水解活性方面的相对效力相似，这表明存在因果关系，磷脂水解产物溶血磷脂和脂肪酸对线粒体孔开放的影响也支持了这一点。这些发现有助于确定导致这些蛇类神经毒素使神经末梢中毒的细胞事件，并表明线粒体损伤是其毒性的重要决定因素。
