Sphingolipid metabolism cooperates with BAK and BAX to promote the mitochondrial pathway of apoptosis.
Sphingolipid metabolism cooperates with BAK and BAX to promote the mitochondrial pathway of apoptosis.
复制标题
DOI：
10.1016/j.cell.2012.01.038
复制
发表时间：
2012-03-02
期刊：
影响因子：
64.5
通讯作者：
Green DR
中科院分区：
文献类型：
--
作者：
Chipuk JE;McStay GP;Bharti A;Kuwana T;Clarke CJ;Siskind LJ;Obeid LM;Green DR
线粒体在功能和物理上与异型膜相关，但对这些相互作用如何影响线粒体外膜透化（MOMP）和凋亡知之甚少。我们观察到异型膜从线粒体的解离抑制巴克/BAX依赖的细胞色素c（cyto c）的释放。与MOMP致敏相关的中性鞘磷脂酶的生化纯化表明鞘脂代谢协调巴克/BAX激活。使用纯化的脂质和酶，通过鞘脂代谢途径的体外重建实现对MOMP的敏感性。鞘脂代谢抑制剂阻断MOMP从重膜制剂，但未能影响MOMP的鞘脂重建，纯化的线粒体的存在下。此外，鞘脂产物鞘氨醇-1-PO 4和十六烯醛分别与巴克和BAX特异性合作。神经鞘脂代谢也是细胞凋亡反应所必需的。我们的研究表明，巴克/BAX激活和细胞凋亡是通过BH 3-only蛋白和一个特定的脂质环境协调的，该脂质环境由异型膜-线粒体相互作用维持
Mitochondria are functionally and physically associated with heterotypic membranes, yet little is known about how these interactions impact mitochondrial outer-membrane permeabilization (MOMP) and apoptosis. We observed that dissociation of heterotypic membranes from mitochondria inhibited BAK/BAX-dependent cytochrome c (cyto c) release. Biochemical purification of neutral sphingomyelinases that correlated with MOMP sensitization suggested that sphingolipid metabolism coordinates BAK/BAX activation. Using purified lipids and enzymes, sensitivity to MOMP was achieved by in vitro reconstitution of the sphingolipid metabolic pathway. Sphingolipid metabolism inhibitors blocked MOMP from heavy membrane preparations but failed to influence MOMP in the presence of sphingolipid-reconstituted, purified mitochondria. Furthermore, the sphingolipid products, sphingosine-1-PO4 and hexadecenal, cooperated specifically with BAK and BAX, respectively. Sphingolipid metabolism was also required for cellular responses to apoptosis. Our studies suggest that BAK/BAX activation and apoptosis are coordinated through BH3-only proteins and a specific lipid milieu that is maintained by heterotypic membrane-mitochondrial interactions
登录
查看更多内容
影响因子：
9
作者：
Kumar, A.;Oskouian, B.;Saba, J. D.
通讯作者：
Saba, J. D.
线粒体富含神经酰胺的宏域在辐照后功能化bax。
影响因子：
3.7
作者：
Lee H;Rotolo JA;Mesicek J;Penate-Medina T;Rimner A;Liao WC;Yin X;Ragupathi G;Ehleiter D;Gulbins E;Zhai D;Reed JC;Haimovitz-Friedman A;Fuks Z;Kolesnick R
通讯作者：
Kolesnick R
影响因子：
12.4
作者：
Bellot, G.;Cartron, P. -F.;Vallette, F. M.
通讯作者：
Vallette, F. M.
影响因子：
8
作者：
Alphonse, G;Bionda, C;Rodriguez-Lafrasse, C
通讯作者：
Rodriguez-Lafrasse, C
DOI：
10.1126/science.1158111
发表时间：
2008-10-03
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Deng X;Yin X;Allan R;Lu DD;Maurer CW;Haimovitz-Friedman A;Fuks Z;Shaham S;Kolesnick R
通讯作者：
Kolesnick R