KDM3A Senses Oxygen Availability to Regulate PGC-1α-Mediated Mitochondrial Biogenesis.
Mol Cell
; 76(6): 885-895.e7, 2019 12 19.
Article
in En
| MEDLINE
| ID: mdl-31629659
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 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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Oxygen
/
Organelle Biogenesis
/
Brain Neoplasms
/
Protein Processing, Post-Translational
/
Jumonji Domain-Containing Histone Demethylases
/
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
/
Mitochondria
Limits:
Animals
/
Female
/
Humans
Language:
En
Journal:
Mol Cell
Journal subject:
BIOLOGIA MOLECULAR
Year:
2019
Type:
Article