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NATURE: cell biology: 功能决定形态

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发表于 2016-2-19 11:41:25 | 显示全部楼层 |阅读模式
The architect Louis Sullivan wrote that, for all things, “form ever follows function”. In keeping with this rule, energy-producing organelles called mitochondria exist in different forms in different cell types1, 2 and under different conditions3. Long, contiguous assemblies of mitochondria promote energy production, whereas stress causes their fragmentation into small, round, disconnected units. Mitochondria switch between these two forms through rounds of fission and fusion4. Writing in Science, Toyama et al.5 identify a signalling pathway that triggers the fission of long mitochondrial assemblies in response to stress.
建筑师沙利文路易斯写道,对于所有的事情,“形态永远遵循功能”。与此规则保持一致,在不同的细胞类型和不同的条件下,能量产生细胞器称为线粒体的存在。长,连续的组件的线粒体促进能源生产,而压力导致他们的分裂成小,圆,断开的单位。通过裂变和融合的方式,通过这2种形式的线粒体交换。富山等在科学杂志中写到,确定一个信号通路,触发了长的线粒体组件的裂变反应应激反应。


The energy status of a cell can be measured by the ratio of AMP molecules (an end product of chemical-energy expenditure) to energy-carrying ATP molecules in the cytoplasm. Mitochondria produce ATP in response to energy depletion. One sensor of energy depletion is an evolutionarily conserved protein known as AMP-activated protein kinase (AMPK). This protein is activated by binding AMP or by stresses that deplete ATP and increase the AMP:ATP ratio, such as glucose deprivation, inadequate blood supply and lack of oxygen6.
一个细胞的能量状态可以通过在细胞质中能量携带的分子ATP与消耗AMP的比例(化学能量消耗的一个最终产物)来衡量。线粒体产生对能量消耗的响应。一个传感器的能源消耗是一个进化上保守的蛋白质称为AMP激活的蛋白激酶(AMPK)。这种蛋白是激活绑定、或通过消耗ATP的应力和增加放大器:ATP比值,如葡萄糖剥夺,血液供应不足和缺乏氧气6


Activation of AMPK enhances the production of mitochondria and improves endurance — indeed, the use of drugs that activate AMPK, such as AICAR, is banned from competitive sports by the World Anti-Doping Agency. AMPK phosphorylates several substrates6, thereby regulating metabolism, mitochondrial proliferation and an intracellular degradation process called autophagy. However, previous studies have not demonstrated whether AMPK directly regulates mitochondrial form.
AMPK的激活增强线粒体生产和提高耐力,实际上,激活AMPK的药物的使用,如AICAR,世界反兴奋剂机构禁止参与体育竞技的药物之一。AMPK的有多个磷酸化亚基6,从而调节代谢、线粒体的增殖和细胞内的降解过程被称为自噬。然而,以往的研究都没有证实是否AMPK直接调节线粒体形态。


Researchers have known for years7 that mitochondria undergo fission and become fragmented in response to poisons such as cyanide, which damage the organelles by inhibiting the electron transport chain (ETC) that drives ATP synthesis. But how such mitochondrial dysfunction is sensed, and how it triggers a rapid fission response, has remained unclear.
研究人员已经知道了线粒体在响应毒物如氰化物的时候会裂变和变得支离破碎,另外损伤的细胞器,通过抑制电子传递链(ETC)等反应驱动ATP的合成。但是,如何检测这些线粒体功能障碍,以及它如何触发一个快速裂变反应,目前还不清楚。


全文链接:http://www.nature.com/nature/journal/v530/n7590/full/530288a.html
Toyama et al. found that AMPK is rapidly activated in response to the ETC-inhibiting drugs rotenone and antimycin A, presumably as a consequence of an increased AMP:ATP ratio. Mitochondria became fragmented in drug-treated cells, but this response was prevented by deletion of the gene that encodes AMPK. By contrast, pharmacological activation of AMPK with AICAR was sufficient to cause fragmentation, demonstrating a surprising link between activation of this sensor protein and mitochondrial fission.
富山等发现AMPK参与快速激活等ETC抑制药物早期反应和鱼藤酮抗霉素A,大概是一个增加AMP:ATP比值的后果。药物处理的细胞中线粒体变得支离破碎,但这种反应是防止编码AMPK基因缺失。相比之下,AICAR活化的AMPK是足以引起碎裂,演示了一个令人惊讶的联系这一传感器激活蛋白和线粒体裂变。


How does AMPK relay signals to the mitochondrial fission machinery? The core mitochondrial fission factor is the enzyme Dynamin-related protein 1 (DRP1), which wraps around constriction sites at the mitochondrial membrane, forming spiral complexes that mediate scission. DRP1 is primarily located in the cytoplasm8, 9, but is recruited to prospective mitochondrial scission sites by receptor proteins such as MFF (ref. 10). Toyama and colleagues showed that AMPK directly phosphorylated MFF at two amino-acid residues, serine-155 (S155) and S172, consistent with results from a previous study11. This modification increased the recruitment of DRP1 to mitochondria (Fig. 1). Furthermore, mutations that blocked MFF phosphorylation prevented poison-mediated mitochondrial fragmentation and DRP1 recruitment
如何传递信号的AMPK的线粒体裂变机械?核心线粒体分裂的因素是酶蛋白相关蛋白1(DRP1),环绕收缩网站在线粒体膜上,形成螺旋复合物介导的断裂。Drp1主要分布在细胞质中,但被招募到前瞻性线粒体断裂位点的是受体蛋白如MFF(参考文献10)。富山和他的同事发现,AMPK磷酸化过程直接在两个氨基酸残基,serine-155(s155)和S172,从以前的研究结果一致。这一修改增加招募Drp1线粒体(图1)。此外,基因突变,防止堵塞MFF磷酸化介导的线粒体分裂和招募Drp1毒药


Thus, the authors have identified a mechanism that regulates mitochondrial form, and probably function. They propose that the increased fission induced by AMPK facilitates selective elimination of the damaged mitochondria through autophagy, which may act as a quality-control response to the poisons. In support of this suggestion, mitochondrial fission has previously been linked to engulfment and elimination of damaged mitochondria by autophagosome structures, which mediate autophagy12. Therefore, the authors' proposal is a plausible explanation for their observations, and deserves further study.
因此,作者已经确定了一种调节线粒体的形式和可能的功能的机制。他们认为增加裂变是由AMPK促进引起的受损的线粒体通过自噬选择性消除,可作为响应毒药的质量控制。为了支持这个建议,线粒体分裂之前已经通过自噬体结构与吞噬和消除受损的线粒体,它介导自噬。因此,作者的建议是一个合理的解释,他们的意见,值得进一步研究。

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 楼主| 发表于 2016-2-19 11:41:48 | 显示全部楼层
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