近日,，國際著名雜志Cell刊登了來自美國紐約西奈山醫(yī)學(xué)院,，圣裘德童研究醫(yī)院等處的研究人員的最新研究成果“Sphingolipid Metabolism Cooperates with BAK and BAX to Promote the Mitochondrial Pathway of Apoptosis”,，在文章中，研究者解析了細(xì)胞凋亡相關(guān)的細(xì)胞色素c釋放，這將為進(jìn)一步揭示細(xì)胞凋亡的秘密提供了重要信息，這一研究成果公布在Cell雜志上,，同期雜志還配發(fā)的相關(guān)點(diǎn)評(píng)文章。
文章的通訊作者分別是西奈山醫(yī)學(xué)院Jerry E. Chipuk,，以及圣猶大兒童研究醫(yī)院Douglas R. Green教授,，其中Green教授是世界著名的免疫學(xué)家，其方向主要是細(xì)胞凋亡或主動(dòng)細(xì)胞死亡的相關(guān)研究,，并探討這一過程在調(diào)控免疫系統(tǒng)中的作用,。Green教授發(fā)表過多篇重要的論文，曾以113篇論文高達(dá)15,，000次的引用率位居全球論文被引用次數(shù)最多的前五名科學(xué)家之列,，其中有兩篇論文的引用次數(shù)位列全球引用次數(shù)最多的論文前25位。
線粒體在功能上和物理結(jié)構(gòu)上都異型膜（heterotypic membranes）存在關(guān)聯(lián),，但是關(guān)于這些相互作用如何影響線粒體外膜通透性（permeabilization，MOMP）,，以及細(xì)胞凋亡的,，目前還知之甚少。
在這篇文章中,，研究人員發(fā)現(xiàn)線粒體異型膜分離能抑制依賴于BAK/BAX的細(xì)胞色素c（cytochrome c）的釋放——細(xì)胞色素C是一種細(xì)胞色素氧化酶,，是電子傳遞鏈中唯一的外周蛋白，位于線粒體內(nèi)側(cè)外膜,，研究發(fā)現(xiàn)細(xì)胞色素C與細(xì)胞凋亡有關(guān),，從線粒體中泄露出的細(xì)胞色素C有誘導(dǎo)細(xì)胞凋亡的作用。
研究人員通過生化方法純化與MOMP敏感性有關(guān)的中性（neutral sphingomyelinases）中性鞘磷脂酶,，發(fā)現(xiàn)脂質(zhì)代謝能調(diào)控BAK/BAX活性,。之后他們又純化了脂質(zhì)和酶，證明通過體外重構(gòu)鞘脂代謝途徑能提高M(jìn)OMP敏感性,。
而且研究人員還發(fā)現(xiàn)脂質(zhì)代謝抑制劑能阻斷重膜準(zhǔn)備中的MOMP,，但不會(huì)影響純鞘重構(gòu)化過的線粒體MOMP。鞘脂產(chǎn)物：sphingosine-1-PO4 和hexadecenal還能與BAK和BAX特異性協(xié)同作用,。
這些都說明了細(xì)胞對(duì)凋亡作出應(yīng)答需要鞘脂代謝(sphingolipid metabolism)的參與,。這項(xiàng)研究也表明BAK/BAX活性和細(xì)胞凋亡能調(diào)控特殊脂質(zhì)環(huán)境，這一環(huán)境是由于異型膜-線粒體相互作用維持的,。（生物谷Bioon.com）
doi:10.1016/j.cell.2012.01.038
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Sphingolipid Metabolism Cooperates with BAK and BAX to Promote the Mitochondrial Pathway of Apoptosis
Jerry E. Chipuk, Gavin P. McStay, Archana Bharti, Tomomi Kuwana, Christopher J. Clarke, Leah J. Siskind, Lina M. Obeid, Douglas R. Green
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.
