1Department of Biomedical Chemistry, School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda, Hyogo 669-1337 Japan.
2Frontiers of Innovative Research in Science and Technology, Konan University, 7-1-20 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 Japan.
Commun Biol. 2019 Jan 3;2:3. doi: 10.1038/s42003-018-0246-9. eCollection 2019.
Mitochondrial damage is caused by changes in the micro-environmental conditions during tumor progression. Cancer cells require mechanisms for mitochondrial quality control during this process; however, how mitochondrial integrity is maintained is unclear. Here we show that E2F3d, a previously unidentified E2F3 isoform, mediates hypoxia-induced mitophagy in cancer cells. Aberrant activity and expression of the E2F3 transcription factor is frequently observed in many cancer cells. Loss of retinoblastoma (Rb) protein family function increases the expression of E2F3d and E2F3a. E2F3d localizes to the outer mitochondrial membrane and its cytosolic domain contains an LC3-interacting region motif. Overexpression of E2F3d induces mitochondrial fragmentation and mitophagy, suggesting that E2F3d plays an important role in mitophagy. Furthermore, depletion of E2F3s attenuates hypoxia-induced mitophagy and increases intracellular levels of reactive oxygen species, which is reversed by the reintroduction of E2F3d. This study presents another key player that regulates mitochondrial quality control in cancer cells.
线粒体损伤是由肿瘤进展过程中微环境条件的变化引起的。在此过程中，癌细胞需要有机制来进行线粒体质量控制；然而，线粒体完整性是如何维持的尚不清楚。在这里，我们发现先前未被识别的 E2F3 异构体 E2F3d 介导了癌细胞中的缺氧诱导的线粒体自噬。E2F3 转录因子的异常活性和表达在许多癌细胞中经常观察到。视网膜母细胞瘤 (Rb) 蛋白家族功能的丧失会增加 E2F3d 和 E2F3a 的表达。E2F3d 定位于外线粒体膜，其胞质结构域含有 LC3 相互作用区域基序。E2F3d 的过表达诱导线粒体碎片化和线粒体自噬，表明 E2F3d 在线粒体自噬中发挥重要作用。此外，E2F3s 的耗竭会减弱缺氧诱导的线粒体自噬，并增加细胞内活性氧的水平，而过表达 E2F3d 则会逆转这种情况。这项研究提出了另一个调节癌细胞中线粒体质量控制的关键因子。
