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

Histone H2AX promotes neuronal health by controlling mitochondrial homeostasis.

Author information

1
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
2
Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
3
Developmental Therapeutics Branch, Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
4
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205; ssnyder@jhmi.edu.
5
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
6
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205.

Abstract

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

PMID:
30910969
PMCID:
PMC6462085
DOI:
10.1073/pnas.1820245116
[Indexed for MEDLINE]
Free PMC Article

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