Mitochondrial degeneration and not apoptosis is the primary cause of embryonic lethality in ceramide transfer protein mutant mice.
Mitochondrial degeneration and not apoptosis is the primary cause of embryonic lethality in ceramide transfer protein mutant mice.
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DOI：
10.1083/jcb.200807176
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发表时间：
2009-01-12
影响因子：
7.8
通讯作者：
Acharya, Jairaj K.
中科院分区：
文献类型：
--
作者：
Wang, Xin;Rao, Raghavendra Pralhada;Kosakowska-Cholody, Teresa;Masood, M. Athar;Southon, Eileen;Zhang, Helin;Berthet, Cyril;Nagashim, Kunio;Veenstra, Timothy K.;Tessarollo, Lino;Acharya, Usha;Acharya, Jairaj K.
神经酰胺转运蛋白（CERT）的功能是将神经酰胺从内质网（ER）转运到高尔基体。在这项研究中，我们表明CERT是小鼠发育和胚胎存活的必需基因，并且非常引人注目的是，对线粒体完整性至关重要。CERT突变胚胎在ER中积累神经酰胺，但也将神经酰胺错误定位于线粒体，损害其功能。突变胚胎中的细胞显示ER异常扩张和线粒体退化。这些亚细胞变化表现为心脏缺陷，并导致心脏功能严重受损和胚胎死亡约11.5天。尽管有神经酰胺的积累，CERT突变小鼠不会因为细胞凋亡的增加而死亡。相反，细胞增殖受损，细胞周期相关蛋白的表达水平改变。单个细胞存活下来，可能是因为细胞存活机制被激活。因此，在CERT突变小鼠中由神经酰胺积累引起的ER和线粒体完整性的整体妥协主要影响器官发生，而不是通过凋亡途径引起细胞死亡。
Ceramide transfer protein (CERT) functions in the transfer of ceramide from the endoplasmic reticulum (ER) to the Golgi. In this study, we show that CERT is an essential gene for mouse development and embryonic survival and, quite strikingly, is critical for mitochondrial integrity. CERT mutant embryos accumulate ceramide in the ER but also mislocalize ceramide to the mitochondria, compromising their function. Cells in mutant embryos show abnormal dilation of the ER and degenerating mitochondria. These subcellular changes manifest as heart defects and cause severely compromised cardiac function and embryonic death around embryonic day 11.5. In spite of ceramide accumulation, CERT mutant mice do not die as a result of enhanced apoptosis. Instead, cell proliferation is impaired, and expression levels of cell cycle–associated proteins are altered. Individual cells survive, perhaps because cell survival mechanisms are activated. Thus, global compromise of ER and mitochondrial integrity caused by ceramide accumulation in CERT mutant mice primarily affects organogenesis rather than causing cell death via apoptotic pathways.
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影响因子：
6.5
作者：
Haberkant, Per;Schmitt, Oliver;Bruegger, Britta
通讯作者：
Bruegger, Britta
影响因子：
64.8
作者：
Karbowski, Mariusz;Norris, Kristi L.;Youle, Richard J.
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影响因子：
15.9
作者：
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56.9
作者：
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通讯作者：
Korsmeyer, SJ
影响因子：
2.6
作者：
CHALLICE, CE;VIRAGH, S
通讯作者：
VIRAGH, S