Back to Search
Start Over
KDM3A Senses Oxygen Availability to Regulate PGC-1α-Mediated Mitochondrial Biogenesis.
- Source :
-
Molecular Cell . Dec2019, Vol. 76 Issue 6, p885-885. 1p. - Publication Year :
- 2019
-
Abstract
- 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 K M 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. • Hypoxia suppresses mitochondrial biogenesis of tumor cells • PGC-1α's activity is inhibited by K224 monomethylation under hypoxic conditions • KDM3A senses oxygen availability for its activity and demethylates PGC-1α • PGC-1α monomethylation reduces hypoxia-induced ROS and apoptosis for tumor growth Qian et al. demonstrated that KDM3A functions as an oxygen sensor and demethylates K224-monomethylated PGC-1α under normoxic conditions. Hypoxia inhibits KDM3A activity and increases PGC-1α K224 monomethylation, resulting in the inhibition of PGC-1α and PGC-1α-dependent mitochondrial biogenesis, a decrease of ROS levels and apoptosis, and the promotion of brain tumor development. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 10972765
- Volume :
- 76
- Issue :
- 6
- Database :
- Academic Search Index
- Journal :
- Molecular Cell
- Publication Type :
- Academic Journal
- Accession number :
- 140423306
- Full Text :
- https://doi.org/10.1016/j.molcel.2019.09.019