KDM3A Senses Oxygen Availability to Regulate PGC-1α-Mediated Mitochondrial Biogenesis
KDM3A Senses Oxygen Availability to Regulate PGC-1α-Mediated Mitochondrial Biogenesis
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KDM3A 感知氧气可用性以调节 PGC-1 α 介导的线粒体生物发生
DOI：
10.1016/j.molcel.2019.09.019
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发表时间：
2019-12-19
期刊：
影响因子：
16
通讯作者：
Lu, Zhimin
中科院分区：
文献类型：
--
作者：
Qian, Xu;Li, Xinjian;Lu, Zhimin
在肿瘤生长期间发生的缺氧引发复杂的适应性反应，其中过氧化物酶体增殖物激活受体γ共激活因子-1 α（PGC-1 α）在线粒体生物发生和氧化代谢中起关键作用。然而，PGC-1 α如何响应氧可用性而调节仍不清楚。我们证明了赖氨酸脱甲基酶3A（KDM 3A）在常氧条件下与PGC-1 α结合并使PGC-1 α的单甲基化赖氨酸（K）224脱甲基。低氧刺激抑制KDM 3A，其具有高的氧K-M活性，并增强PGC-1 α K224单甲基化。这种修饰降低了TFAM、TFB 1 M和TFB 2 M的NRF 1和NRF 2依赖性转录调控所需的PGC-1 α活性，导致线粒体生物合成减少。PGC-1 α K224 R突变体的表达显著增加了缺氧条件下的线粒体生物合成、活性氧（ROS）产生和肿瘤细胞凋亡，并抑制了小鼠脑肿瘤的生长。这项研究表明，PGC-1 α单甲基化依赖于氧可用性调节的KDM 3A，在线粒体生物合成的调节中起着关键作用。
Hypoxia, which occurs during tumor growth, triggers complex adaptive responses in which peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) plays a critical role in mitochondrial biogenesis and oxidative metabolism. However, how PGC-1 alpha is regulated in response to oxygen availability remains unclear. We demonstrated that lysine demethylase 3A (KDM3A) binds to PGC-1 alpha and demethylates monomethylated lysine (K) 224 of PGC-1a under normoxic conditions. Hypoxic stimulation inhibits KDM3A, which has a high K-M of oxygen for its activity, and enhances PGC-1 alpha K224 monomethylation. This modification decreases PGC-1 alpha's activity required for NRF1- and NRF2-dependent transcriptional regulation of TFAM, TFB1M, and TFB2M, resulting in reduced mitochondrial biogenesis. Expression of PGC-1 alpha K224R mutant significantly increases mitochondrial biogenesis, reactive oxygen species (ROS) production, and tumor cell apoptosis under hypoxia and inhibits brain tumor growth in mice. This study revealed that PGC-1 alpha monomethylation, which is dependent on oxygen availability-regulated KDM3A, plays a critical role in the regulation of mitochondrial biogenesis.