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陕西快乐十分软件下载:Histone H2AX promotes neuronal health by controlling mitochondrial homeostasis
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Histone H2AX elicits proper DNA repair through its phosphorylation by ataxia-telangiectasia mutated (ATM) kinase. While ATM senses reactive oxygen species, the role of H2AX in the maintenance of redox homeostasis remains unknown. Here we establish that H2AX deletion leads to impairment of mitochondrial function and repression of the mitochondrial biogenesis gene PGC-1α. Restoring PGC-1α abrogates mitochondrial deficits and mitigates cell death. This study unveils a role for H2AX in mitochondrial homeostasis associated with neuroprotection.
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.
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Author contributions: U.W. and S.H.S. designed research; U.W., B.D.P., D.B., A.P.M., M.B., and M.M.H. performed research; W.M.B. contributed new reagents/analytic tools; U.W. and S.H.S. analyzed data; and U.W. and S.H.S. wrote the paper.
Reviewers: O.A.M., Peter MacCallum Cancer Centre; and R.S., University of Maryland School of Medicine.
Conflict of interest statement: U.W. and O.A.M. are coauthors on a 2016 article; they did not collaborate directly on the paper. The authors declare no competing financial interests.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1820245116/-/DCSupplemental.
Published under the PNAS license.