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蝰蛇毒液中的神经毒性分泌型磷脂酶 A 靶向神经元线粒体中的细胞色素 c 氧化酶。

The neurotoxic secreted phospholipase A from the Vipera a. ammodytes venom targets cytochrome c oxidase in neuronal mitochondria.

机构信息

Department of Molecular and Biomedical Sciences, Jožef Stefan Institute, Jamova 39, 1000, Ljubljana, Slovenia.

Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000, Ljubljana, Slovenia.

出版信息

Sci Rep. 2019 Jan 22;9(1):283. doi: 10.1038/s41598-018-36461-6.

DOI:10.1038/s41598-018-36461-6
PMID:30670719
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6342964/
Abstract

The β-neurotoxic secreted phospholipases A (sPLAs) block neuro-muscular transmission by poisoning nerve terminals. Damage inflicted by such sPLAs (β-ntx) on neuronal mitochondria is characteristic, very similar to that induced by structurally homologous endogenous group IIA sPLA when its activity is elevated, as, for example, in the early phase of Alzheimer's disease. Using ammodytoxin (Atx), the β-ntx from the venom of the nose-horned viper (Vipera a. ammodytes), the sPLA receptor R25 has been detected in neuronal mitochondria. This receptor has been purified from porcine cerebral cortex mitochondria by a new Atx-affinity-based chromatographic procedure. Mass spectrometry analysis revealed R25 to be the subunit II of cytochrome c oxidase (CCOX), an essential constituent of the respiratory chain complex. CCOX was confirmed as being the first intracellular membrane receptor for sPLA by alternative Atx-affinity-labellings of purified CCOX, supported also by the encounter of Atx and CCOX in PC12 cells. This discovery suggests the explanation of the mechanism by which β-ntx hinders production of ATP in poisoned nerve endings. It also provides a new insight into the potential function and dysfunction of endogenous GIIA sPLA in mitochondria.

摘要

β-神经毒性分泌型磷脂酶 A（sPLAs）通过毒害神经末梢来阻断神经肌肉传递。这种 sPLA（β-ntx）对神经元线粒体造成的损伤是特征性的，与结构同源的内源性 IIA 组 sPLA 当其活性升高时诱导的损伤非常相似，例如在阿尔茨海默病的早期阶段。使用来自角鼻蝰（Vipera a. ammodytes）毒液的氨甲蝶呤（Atx），已经在神经元线粒体中检测到 sPLA 受体 R25。该受体已通过新的基于 Atx 亲和力的色谱程序从猪大脑皮质线粒体中纯化出来。质谱分析表明 R25 是细胞色素 c 氧化酶（CCOX）的亚基 II，CCOX 是呼吸链复合物的必需组成部分。通过纯化的 CCOX 的替代 Atx 亲和力标记以及在 PC12 细胞中 Atx 和 CCOX 的相遇，证实了 CCOX 是 sPLA 的第一个细胞内膜受体。这一发现为解释β-ntx 如何阻碍中毒神经末梢中 ATP 的产生提供了一种机制。它还为内源性 GIIA sPLA 在线粒体中的潜在功能和功能障碍提供了新的见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/04ce/6342964/4ad2b7a50f54/41598_2018_36461_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/04ce/6342964/6ade1bd75ce0/41598_2018_36461_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/04ce/6342964/3744dbc54161/41598_2018_36461_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/04ce/6342964/051b7f6bce5b/41598_2018_36461_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/04ce/6342964/a2240ee2464a/41598_2018_36461_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/04ce/6342964/2aa98a6951e3/41598_2018_36461_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/04ce/6342964/4ad2b7a50f54/41598_2018_36461_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/04ce/6342964/6ade1bd75ce0/41598_2018_36461_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/04ce/6342964/3744dbc54161/41598_2018_36461_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/04ce/6342964/051b7f6bce5b/41598_2018_36461_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/04ce/6342964/a2240ee2464a/41598_2018_36461_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/04ce/6342964/2aa98a6951e3/41598_2018_36461_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/04ce/6342964/4ad2b7a50f54/41598_2018_36461_Fig6_HTML.jpg

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