Cunniff Brian, McKenzie Andrew J, Heintz Nicholas H, Howe Alan K
Department of Pathology, University of Vermont, Burlington, VT 05405 University of Vermont Cancer Center, University of Vermont, Burlington, VT 05405.
University of Vermont Cancer Center, University of Vermont, Burlington, VT 05405 Department of Pharmacology, University of Vermont, Burlington, VT 05405.
Mol Biol Cell. 2016 Sep 1;27(17):2662-74. doi: 10.1091/mbc.E16-05-0286. Epub 2016 Jul 6.
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.
细胞迁移是一种复杂的行为，涉及许多消耗能量的生化事件，这些事件反复改变细胞形状和位置。线粒体是细胞ATP的主要生产者，是动态细胞器，会融合、分裂并重新定位以响应细胞代谢需求。以卵巢癌细胞为模型，我们发现线粒体积极渗透到前沿板状伪足中，从而增加局部线粒体质量和相对ATP浓度，并支持瓦伯格效应向有氧糖酵解的局部逆转。这与AMP激活蛋白激酶（AMPK）的伪足活性增加相关，AMPK是一种至关重要的细胞能量传感器和代谢调节剂。此外，AMPK的局部药理学激活增加了前沿线粒体通量、ATP含量和细胞骨架动力学，而AMPK的光遗传学抑制则在细胞迁移和三维细胞外基质侵袭过程中阻止线粒体运输。这些观察结果表明，AMPK在细胞迁移和侵袭过程中将局部能量需求与线粒体的亚细胞靶向联系起来。
