AMPK activity regulates trafficking of mitochondria to the leading edge during cell migration and matrix invasion.
AMPK activity regulates trafficking of mitochondria to the leading edge during cell migration and matrix invasion.
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DOI：
10.1091/mbc.e16-05-0286
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发表时间：
2016-09-01
影响因子：
3.3
通讯作者：
Howe AK
中科院分区：
文献类型：
--
作者：
Cunniff B;McKenzie AJ;Heintz NH;Howe AK
线粒体浸润前缘板状伪足，增加局部线粒体质量和相对ATP浓度。AMPK调节线粒体向2D板状伪足和3D侵入伪足前缘的浸润，将局部代谢传感与细胞运动期间线粒体的亚细胞靶向耦合。细胞迁移是一种复杂的行为，涉及许多能量昂贵的生化事件，反复改变细胞的形状和位置。线粒体是细胞ATP的主要生产者，是动态的细胞器，其融合、分裂和重新定位以响应细胞代谢需求。使用卵巢癌细胞作为模型，我们表明，线粒体积极渗透前缘板状伪足，从而增加局部线粒体质量和相对ATP浓度，并支持局部逆转的瓦尔堡转向有氧糖酵解。这与AMP活化蛋白激酶（AMPK）的伪足活性增加相关，AMPK是一种非常重要的细胞能量传感器和代谢调节因子。此外，AMPK的局部药理学激活增加前沿线粒体通量、ATP含量和细胞骨架动力学，而AMPK的光遗传学抑制在三维细胞外基质的迁移和侵入期间停止线粒体运输。这些观察结果表明，AMPK夫妇的局部能量需求的线粒体在细胞迁移和入侵的亚细胞靶向。
Mitochondria infiltrate leading edge lamellipodia, increasing local mitochondrial mass and relative ATP concentration. AMPK regulates infiltration of mitochondria into the leading edge of 2D lamellipodia and 3D invadopodia, coupling local metabolic sensing to subcellular targeting of mitochondria during cell movement. Cell migration is a complex behavior involving many energy-expensive biochemical events that iteratively alter cell shape and location. Mitochondria, the principal producers of cellular ATP, are dynamic organelles that fuse, divide, and relocate to respond to cellular metabolic demands. Using ovarian cancer cells as a model, we show that mitochondria actively infiltrate leading edge lamellipodia, thereby increasing local mitochondrial mass and relative ATP concentration and supporting a localized reversal of the Warburg shift toward aerobic glycolysis. This correlates with increased pseudopodial activity of the AMP-activated protein kinase (AMPK), a critically important cellular energy sensor and metabolic regulator. Furthermore, localized pharmacological activation of AMPK increases leading edge mitochondrial flux, ATP content, and cytoskeletal dynamics, whereas optogenetic inhibition of AMPK halts mitochondrial trafficking during both migration and the invasion of three-dimensional extracellular matrix. These observations indicate that AMPK couples local energy demands to subcellular targeting of mitochondria during cell migration and invasion.