【drug-news】PNAS：线粒体是雷帕霉素的靶点
Ramanathan and Schreiber present a mechanism of action for mTOR (mammalian target of rapamycin), a protein kinase that acts in protein complexes to regulate metabolism. A transcriptionally mediated mechanism for control of mitochondrial function has been proposed, but Ramanathan and Schreiber find evidence for a rapid direct effect of mTOR at the membrane of the mitochondria. In human Jurkat cells (a leukemic T cell line), a global screen of intracellular metabolites showed that treatment of cells with rapamycin (to inhibit mTOR function) caused changes indicative of decreased mitochondrial respiration and increased aerobic glycolysis. The metabolic profile of such rapamycin-treated cells was similar to that of cells treated with a pharmacological inhibitor of VDAC2, a mitochondrial membrane protein that mediates substrate transport into mitochondria. Immunoprecipitation experiments showed that mTOR was associated with VDAC1 and with Bcl-xl, a regulatory protein that functions in control of apoptosis and of substrate permeability in the mitochondria. Bcl-xl was phosphorylated in vitro by mTOR, indicating that it might be regulated by mTOR. Treatment of cells with rapamycin caused decreased association of Bcl-xl with mTOR, and a pharmacological inhibitor of the interaction of Bcl-xl (and that of other Bcl proteins) with other proteins also inhibited mitochondrial respiration, whereas overexpression of Bcl-xl made cells less sensitive to mitochondrial effects of rapamycin. The authors, therefore, propose that the mTOR complex may function as a switch at the mitochondrial membrane that regulates the balance between glycolytic and respiratory metabolism. They also note that rapamycin is an effective treatment for certain cancers and better understanding of its effects may help identify susceptible cancers and allow combined therapies that exploit the increased dependence of rapamycin-treated cells on aerobic glycolysis.
http://stke.sciencemag.org/cgi/content/abstract/sigtrans;3/103/ec5 原文
A. Ramanathan, S. L. Schreiber, Direct control of mitochondrial function by mTOR. Proc. Natl. Acad. Sci. U.S.A. 106, 22229–22232 (2009)（见附件）.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1087961/?tool=pubmed
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寿命故事
雷帕霉素相关的mTOR通路与利用氨基酸合成蛋白质有关（见附图）。因此，雷帕霉素延长寿命与附录一限制必需氨基酸延长寿命的机理是一样的，即抑制mTOR通路。
实际上节制热量（附录二）也可以抑制mTOR通路（Kaeberlein et al 2009）。
楼上报道的Ramanathan等人（2009）的研究表明，对mTOR的抑制可以将氧化磷酸化转化为有氧糖酵解。后者就是癌细胞中发生的著名的Warburg效应。值得注意的是，正常细胞与癌细胞是有区别的。低糖可以饿死癌细胞，但有利于正常细胞（附录二）。
参考文献
Kaeberlein M, Kapahi P. 2009. Cell signaling. Aging is RSKy business. Science. 2009 Oct 2;326(5949):55-6.
http://www.sciencemag.org/cgi/content/full/sci;326/5949/55 附录一 【bio-news】Nature online: 果蝇寿命实验揭示必需氨基酸的真正含义
http://www.dxy.cn/bbs/post/view?bid=116&id=16091877&tpg=1&ppg=1&sty=1#16091878
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作者:admin@医学,生命科学 2010-12-26 12:22
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