Histone H2AX promotes neuronal health by controlling mitochondrial homeostasis

Proc Natl Acad Sci U S A. 2019 Apr 9;116(15):7471-7476. doi: 10.1073/pnas.1820245116. Epub 2019 Mar 25.


Phosphorylation of histone H2AX is a major contributor to efficient DNA repair. We recently reported neurobehavioral deficits in mice lacking H2AX. Here we establish that this neural failure stems from impairment of mitochondrial function and repression of the mitochondrial biogenesis gene PGC-1α. H2AX loss leads to reduced levels of the major subunits of the mitochondrial respiratory complexes in mouse embryonic fibroblasts and in the striatum, a brain region particularly vulnerable to mitochondrial damage. These defects are substantiated by disruption of the mitochondrial shape in H2AX mutant cells. Ectopic expression of PGC-1α restores mitochondrial oxidative phosphorylation complexes and mitigates cell death. H2AX knockout mice display increased neuronal death in the brain when challenged with 3-nitropronionic acid, which targets mitochondria. This study establishes a role for H2AX in mitochondrial homeostasis associated with neuroprotection.

Keywords: DNA repair; histone H2AX; mitochondrial homeostasis; neuroprotection; oxidative stress.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Death
  • Electron Transport / physiology
  • Histones / genetics
  • Histones / metabolism*
  • Mice
  • Mice, Knockout
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Neural Stem Cells / cytology
  • Neural Stem Cells / metabolism*
  • Neurons / cytology
  • Neurons / metabolism*
  • Oxidative Phosphorylation*
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / genetics
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism
  • Phosphorylation


  • H2AX protein, mouse
  • Histones
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse