线粒体是细胞内最大的耗氧细胞器和主要能量供应中心，在肿瘤细胞适应低氧中发挥重要作用。低氧可导致线粒体损伤，诱发凋亡阻碍肿瘤细胞存活。肿瘤细胞如何感知低氧，主动调节线粒体生物合成来适应生存尚不清楚。PGC-1α是线粒体生物合成的最主要调节因子。本项目前期研究发现，低氧通过抑制去甲基化酶KDM3A活性促进PGC-1αK224甲基化；进一步研究发现，该甲基化抑制线粒体生物合成。在此基础上，我们提出“低氧可能通过调节甲基转移酶和/或去甲基化酶活性来促进PGC-1αK224甲基化，抑制下游转录因子及关键信号通路活化来影响线粒体生物合成，减少能量物质消耗及ROS等有害代谢产物产生，驱动胶质瘤生存”的科学假说。本项目将从体内外实验到临床分析全面阐明以PGC-1α作为关键节点在低氧调控胶质瘤线粒体生物合成中的作用机制。本研究成果将揭示胶质瘤细胞适应低氧的重要调节机制，也为靶向和阻断该机制提供理论依据。

Mitochondria, the largest oxygen consuming organelles and the main energy supplier in cells, play important roles in the adaptation of tumor cells to hypoxia. Hypoxia results in mitochondrial damage and apoptosis, hindering the survival of tumor cells. How tumor cells sense hypoxia and actively regulate mitochondrial biosynthesis to promote survival is unclear. PGC-1α is the master regulator of mitochondrial biosynthesis. Our preliminary studies found that hypoxia promoted PGC-1αK224 methylation by inhibiting the activity of demethylase KDM3A. Meanwhile, this methylation inhibited mitochondrial biosynthesis. Base on these results, we hypothesizes that hypoxia promotes PGC-1αK224 monomethylation and inhibits the activation of downstream transcription factors by regulating methyltransferase and/or demethylase activity, thereby regulating mitochondrial biosynthesis, reducing energy consumption and ROS production, and driving glioma cell survival. This project will comprehensively elucidate the mechanisms of PGC-1α as a key node in the regulation of mitochondrial biosynthesis in glioma from cell levels, animal model to clinical analysis. This study will reveal the vital regulatory mechanism for glioma cells to adapt to the hypoxic microenvironment, and provide theoretical basis for targeting and blocking this mechanism.