Transient Hypoxia Stimulates Mitochondrial Biogenesis in Brain Subcortex by a Neuronal Nitric Oxide Synthase-Dependent Mechanism
Open Access
- 27 February 2008
- journal article
- Published by Society for Neuroscience in Journal of Neuroscience
- Vol. 28 (9), 2015-2024
- https://doi.org/10.1523/jneurosci.5654-07.2008
Abstract
The adaptive mechanisms that protect brain metabolism during and after hypoxia, for instance, during hypoxic preconditioning, are coordinated in part by nitric oxide (NO). We tested the hypothesis that acute transient hypoxia stimulates NO synthase (NOS)-activated mechanisms of mitochondrial biogenesis in the hypoxia-sensitive subcortex of wild-type (Wt) and neuronal NOS (nNOS) and endothelial NOS (eNOS)-deficient mice. Mice were exposed to hypobaric hypoxia for 6 h, and changes in immediate hypoxic transcriptional regulation of mitochondrial biogenesis was assessed in relation to mitochondrial DNA (mtDNA) content and mitochondrial density. There were no differences in cerebral blood flow or hippocampal PO2responses to acute hypoxia among these strains of mice. In Wt mice, hypoxia increased mRNA levels for peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1 α), nuclear respiratory factor-1, and mitochondrial transcription factor A. After 24 h, new mitochondria, localized in reporter mice expressing mitochondrial green fluorescence protein, were seen primarily in hippocampal neurons.eNOS−/−mice displayed lower basal levels but maintained hypoxic induction of these transcripts. In contrast, nuclear transcriptional regulation of mitochondrial biogenesis innNOS−/−mice was normal at baseline but did not respond to hypoxia. After hypoxia, subcortical mtDNA content increased in Wt andeNOS−/−mice but not innNOS−/−mice. Hypoxia stimulated PGC-1α protein expression and phosphorylation of protein kinase A and cAMP response element binding (CREB) protein in Wt mice, but CREB only was activated ineNOS−/−mice and not innNOS−/−mice. These findings demonstrate that hypoxic preconditioning elicits subcortical mitochondrial biogenesis by a novel mechanism that requires nNOS regulation of PGC-1α and CREB.This publication has 46 references indexed in Scilit:
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