Direct inhibition of mitochondrial respiratory chain complex III by cell-permeable ceramide
Direct inhibition of mitochondrial respiratory chain complex III by cell-permeable ceramide
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DOI：
10.1074/jbc.272.39.24154
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发表时间：
1997-09-26
影响因子：
4.8
通讯作者：
Hoppel, CL
中科院分区：
文献类型：
--
作者：
Gudz, TI;Tserng, KY;Hoppel, CL
神经酰胺是介导肿瘤坏死因子a作用的脂质第二信使！神经酰胺被认为通过激活蛋白磷酸酶、脯氨酸导向的蛋白激酶或蛋白激酶C起作用。肿瘤坏死因子α诱导的细胞凋亡的共同途径与线粒体的早期损伤有关。在本文中，我们证明神经酰胺可以直接抑制线粒体呼吸链功能。在分离的线粒体中，在N-乙酰鞘氨醇（C-2-神经酰胺）（一种合成的细胞可渗透的神经酰胺类似物）存在下，线粒体氧化磷酸化迅速下降。对神经酰胺作用的研究表明，C-2-神经酰胺可降低呼吸链复合体Ⅲ的活性，在下午5-7时达到半数最大效应。相反，N-乙酰神经鞘氨醇（C-2-二氢神经酰胺），它缺乏一个功能关键的双键，在细胞中是无效的，不改变线粒体呼吸或复合物III的活性。我们认为，这些体外观察可能为确定体内线粒体功能调节的新机制奠定基础。
Ceramide is a lipid second messenger that mediates the effects of tumor necrosis factor a! and other agents on cell growth and differentiation, Ceramide is believed to act via activation of protein phosphatase, proline-directed protein kinase, or protein kinase C, Tumor necrosis factor alpha-induced common pathway of apoptosis is associated with am early impairment of mitochondria. Herein, we demonstrate that ceramide earn directly inhibit mitochondrial respiratory chain function, In isolated mitochondria, a rapid decline of mitochondrial oxidative phosphorylation occurs in the presence of N-acetylsphingosine (C-2-ceramide), a synthetic cell-permeable ceramide analog. An investigation of the Bite of ceramide action revealed that tbe activity of respiratory chain complex III is reduced by C-2-ceramide with half-maximum effect al 5-7 PM. in contrast, N-acetylsphinganine (C-2-dihydroceramide), which lacks a functionally critical double bond and is ineffective in cells, did not alter mitochondrial respiration or complex III activity. We suggest that these in vitro observations may set the stage for identifying a novel mechanism of regulation of mitochondrial function in vivo.