Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada.
Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada.
Cell Rep. 2017 Oct 3;21(1):1-9. doi: 10.1016/j.celrep.2017.09.026.
Reactive oxygen species (ROS) are continuously produced as a by-product of mitochondrial metabolism and eliminated via antioxidant systems. Regulation of mitochondrially produced ROS is required for proper cellular function, adaptation to metabolic stress, and bypassing cellular senescence. Here, we report non-canonical regulation of the cellular energy sensor AMP-activated protein kinase (AMPK) by mitochondrial ROS (mROS) that functions to maintain cellular metabolic homeostasis. We demonstrate that mitochondrial ROS are a physiological activator of AMPK and that AMPK activation triggers a PGC-1α-dependent antioxidant response that limits mitochondrial ROS production. Cells lacking AMPK activity display increased mitochondrial ROS levels and undergo premature senescence. Finally, we show that AMPK-PGC-1α-dependent control of mitochondrial ROS regulates HIF-1α stabilization and that mitochondrial ROS promote the Warburg effect in cells lacking AMPK signaling. These data highlight a key function for AMPK in sensing and resolving mitochondrial ROS for stress resistance and maintaining cellular metabolic balance.
活性氧 (ROS) 是线粒体代谢的副产品，可通过抗氧化系统消除。线粒体产生的 ROS 的调节对于正常的细胞功能、适应代谢应激和避免细胞衰老都是必需的。在这里，我们报告了细胞能量传感器 AMP 激活的蛋白激酶 (AMPK) 受到线粒体 ROS (mROS) 的非经典调节，这种调节作用是为了维持细胞代谢的平衡。我们证明了线粒体 ROS 是 AMPK 的生理激活剂，并且 AMPK 的激活触发了 PGC-1α 依赖性抗氧化反应，从而限制了线粒体 ROS 的产生。缺乏 AMPK 活性的细胞显示线粒体 ROS 水平升高，并提前衰老。最后，我们表明，AMPK-PGC-1α 依赖性控制线粒体 ROS 调节 HIF-1α 的稳定，并且线粒体 ROS 促进缺乏 AMPK 信号的细胞中的瓦伯格效应。这些数据突出了 AMPK 在感知和解决线粒体 ROS 以抵抗应激和维持细胞代谢平衡方面的关键功能。
