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

Mol Cell. 2019 Dec 19;76(6):885-895.e7. doi: 10.1016/j.molcel.2019.09.019. Epub 2019 Oct 16.

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.

Keywords: KDM3A; PGC-1α; hypoxia; mitochondrial biogenesis; monomethylation; oxygen sensing; tumorigenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Brain Neoplasms / enzymology*
  • Brain Neoplasms / genetics
  • Brain Neoplasms / pathology
  • Cell Proliferation
  • Female
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • HeLa Cells
  • Hep G2 Cells
  • Humans
  • Jumonji Domain-Containing Histone Demethylases / genetics
  • Jumonji Domain-Containing Histone Demethylases / metabolism*
  • Methylation
  • Mice, Inbred BALB C
  • Mice, Nude
  • Mitochondria / enzymology*
  • Mitochondria / pathology
  • Organelle Biogenesis*
  • Oxygen / metabolism*
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / genetics
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism*
  • Protein Processing, Post-Translational*
  • Reactive Oxygen Species / metabolism
  • Signal Transduction
  • Tumor Burden
  • Tumor Hypoxia
  • Tumor Microenvironment

Substances

  • PPARGC1A protein, human
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Reactive Oxygen Species
  • Jumonji Domain-Containing Histone Demethylases
  • KDM3A protein, human
  • Oxygen