Aurora kinase A localises to mitochondria to control organelle dynamics and energy production.
Aurora kinase A localises to mitochondria to control organelle dynamics and energy production.
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DOI：
10.7554/elife.38111
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发表时间：
2018-08-02
期刊：
影响因子：
7.7
通讯作者：
Tramier M
中科院分区：
文献类型：
--
作者：
Bertolin G;Bulteau AL;Alves-Guerra MC;Burel A;Lavault MT;Gavard O;Le Bras S;Gagné JP;Poirier GG;Le Borgne R;Prigent C;Tramier M
许多上皮性癌症显示出与丝氨酸/苏氨酸激酶Aurora A （AURKA）过表达密切相关的细胞周期功能障碍。它在有丝分裂过程中的作用已被广泛描述，并且出现了新的AURKA功能的证据。在这里，我们揭示了AURKA在几种人类癌细胞系的线粒体中被定位和输入。线粒体AURKA影响两个细胞器功能：线粒体动力学和能量产生。当AURKA在间期以内源性水平表达时，它独立于RALA诱导线粒体断裂。相反，当AURKA过表达时，它会增强线粒体融合和ATP的产生。我们证明AURKA直接调节线粒体功能，并且AURKA过表达通过增加线粒体互联性促进代谢重编程。我们的工作为基于同时靶向线粒体功能和AURKA抑制的抗癌治疗铺平了道路。线粒体结构通过将氧气和糖转化为化学能来为细胞提供能量。每个细胞都有数千个线粒体，它们一起工作以提供不断变化的能量需求。它们可以融合在一起，也可以分开，形成大小不同的网络，产生不同数量的能量。保持平衡至关重要；如果能量水平过低，细胞将无法生长和分裂。如果能量水平过高，细胞会以更快的速度生长，这可能会导致细胞癌变。虽然我们知道线粒体提供能量，但我们并不清楚它们是如何通过交流来微调能量供应的。一些线索来自癌细胞，这些癌细胞似乎依赖于它们的线粒体来生存。在这些细胞中，一种叫做AURKA的蛋白质水平高于正常水平。AURKA帮助细胞分裂，并与许多不同的蛋白质相互作用。这种复杂性使得我们很难确切地弄清楚AURKA的作用，但它有可能在能源供应中发挥作用。Bertolin等人现在研究了线粒体是否使用AURKA在人类乳腺癌细胞内进行通讯。用荧光标记标记AURKA蛋白显示它在线粒体内积累。一旦到达那里，AURKA就会改变线粒体的形状，这对它们产生能量的能力产生了巨大的影响。在正常水平下，AURKA会导致线粒体分裂，分裂成更小的片段。这使它们的能量输出保持在正常水平。如果AURKA水平过高，线粒体就会融合在一起，产生更多的能量。这意味着AURKA可以帮助促进快速生长的癌细胞。目前旨在通过阻断AURKA活性来治疗癌症的药物效果不佳。这部分是由于蛋白质在细胞中有许多不同的作用。发现AURKA影响线粒体是了解其未知作用的第一步。这也暗示了开发新药的可能性，以改变含有高水平AURKA的癌细胞中线粒体产生能量的方式。
Many epithelial cancers show cell cycle dysfunction tightly correlated with the overexpression of the serine/threonine kinase Aurora A (AURKA). Its role in mitotic progression has been extensively characterised, and evidence for new AURKA functions emerges. Here, we reveal that AURKA is located and imported in mitochondria in several human cancer cell lines. Mitochondrial AURKA impacts on two organelle functions: mitochondrial dynamics and energy production. When AURKA is expressed at endogenous levels during interphase, it induces mitochondrial fragmentation independently from RALA. Conversely, AURKA enhances mitochondrial fusion and ATP production when it is over-expressed. We demonstrate that AURKA directly regulates mitochondrial functions and that AURKA over-expression promotes metabolic reprogramming by increasing mitochondrial interconnectivity. Our work paves the way to anti-cancer therapeutics based on the simultaneous targeting of mitochondrial functions and AURKA inhibition. Structures called mitochondria power cells by turning oxygen and sugar into chemical energy. Each cell can have thousands of mitochondria, which work together to supply changing energy demands. They can fuse together or break apart, forming networks that change size and produce different amounts of energy. Getting the balance right is crucial; if energy levels are too low, the cell will not be able to grow and divide. If energy levels are too high, the cell can grow at a faster rate, which can contribute to the cell becoming cancerous. Although we know that mitochondria provide energy, it is not clear how they communicate to fine-tune the supply. Some clues come from cancer cells that seem dependent on their mitochondria for survival. In these cells, levels of a protein called AURKA are higher than normal. AURKA helps cells to divide, and it interacts with many different proteins. This complexity makes it difficult to work out exactly what AURKA does, but it is possible that it plays a role in energy supply. Bertolin et al. have now investigated whether mitochondria use AURKA to communicate inside human breast cancer cells. Tagging AURKA proteins with a fluorescent marker revealed that it accumulates inside mitochondria. Once it gets there, AURKA changes the shape of the mitochondria, which has dramatic effects on their capacity to produce energy. At normal levels, AURKA causes the mitochondria to fragment, breaking apart into smaller pieces. This maintains their energy output at a normal level. If AURKA levels are too high, the mitochondria fuse together and produce more energy. This means AURKA could help to fuel fast-growing cancer cells. Current drugs that aim to treat cancer by blocking the activity of AURKA show poor results. This is partly due to the fact that the protein has so many different roles in the cell. Finding that AURKA affects mitochondria is the first step in understanding one of its unknown roles. It also suggests the possibility of developing new drugs to change how mitochondria make energy in cancer cells that contain high levels of AURKA.