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KDM3A Senses Oxygen Availability to Regulate PGC-1α-Mediated Mitochondrial Biogenesis, Mol Cell, 19 Dec 2019

Updated: 2019-12-19

Molecular Cell, 19 December, 2019,DOI:https://doi.org/10.1016/j.molcel.2019.09.019

 

KDM3A Senses Oxygen Availability to Regulate PGC-1α-Mediated Mitochondrial Biogenesis

 

Xu Qian, Xinjian Li, Zhumei Shi, Xiaoming Bai, Yan Xia, Yanhua Zheng, Daqian Xu, Feng Chen, Yongping You, Jing Fang, Zhibin Hu, Qin Zhou, Zhimin Lu

 

Summary

 

Hypoxia, which occurs during tumor growth, triggers complex adaptive responses in which peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) plays a critical role in mitochondrial biogenesis and oxidative metabolism. However, how PGC-1α is regulated in response to oxygen availability remains unclear. We demonstrated that lysine demethylase 3A (KDM3A) binds to PGC-1α and demethylates monomethylated lysine (K) 224 of PGC-1α under normoxic conditions. Hypoxic stimulation inhibits KDM3A, which has a high KM of oxygen for its activity, and enhances PGC-1α K224 monomethylation. This modification decreases PGC-1α’s activity required for NRF1- and NRF2-dependent transcriptional regulation of TFAM, TFB1M, and TFB2M, resulting in reduced mitochondrial biogenesis. Expression of PGC-1α 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-1α monomethylation, which is dependent on oxygen availability-regulated KDM3A, plays a critical role in the regulation of mitochondrial biogenesis.

 

Article link:https://www.sciencedirect.com/science/article/pii/S1097276519307245?via%3Dihub

 

 

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