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Transient hypoxia stimulates mitochondrial biogenesis in brain subcortex by a neuronal nitric oxide synthase-dependent mechanism.
J Neurosci. 2008 Feb 27; 28(9):2015-24.JN

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 PO2 responses to acute hypoxia among these strains of mice. In Wt mice, hypoxia increased mRNA levels for peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1 alpha), 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 in nNOS-/- mice was normal at baseline but did not respond to hypoxia. After hypoxia, subcortical mtDNA content increased in Wt and eNOS-/- mice but not in nNOS-/- mice. Hypoxia stimulated PGC-1alpha protein expression and phosphorylation of protein kinase A and cAMP response element binding (CREB) protein in Wt mice, but CREB only was activated in eNOS-/- mice and not in nNOS-/- mice. These findings demonstrate that hypoxic preconditioning elicits subcortical mitochondrial biogenesis by a novel mechanism that requires nNOS regulation of PGC-1alpha and CREB.

Authors+Show Affiliations

Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

18305236

Citation

Gutsaeva, Diana R., et al. "Transient Hypoxia Stimulates Mitochondrial Biogenesis in Brain Subcortex By a Neuronal Nitric Oxide Synthase-dependent Mechanism." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 28, no. 9, 2008, pp. 2015-24.
Gutsaeva DR, Carraway MS, Suliman HB, et al. Transient hypoxia stimulates mitochondrial biogenesis in brain subcortex by a neuronal nitric oxide synthase-dependent mechanism. J Neurosci. 2008;28(9):2015-24.
Gutsaeva, D. R., Carraway, M. S., Suliman, H. B., Demchenko, I. T., Shitara, H., Yonekawa, H., & Piantadosi, C. A. (2008). Transient hypoxia stimulates mitochondrial biogenesis in brain subcortex by a neuronal nitric oxide synthase-dependent mechanism. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 28(9), 2015-24. https://doi.org/10.1523/JNEUROSCI.5654-07.2008
Gutsaeva DR, et al. Transient Hypoxia Stimulates Mitochondrial Biogenesis in Brain Subcortex By a Neuronal Nitric Oxide Synthase-dependent Mechanism. J Neurosci. 2008 Feb 27;28(9):2015-24. PubMed PMID: 18305236.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Transient hypoxia stimulates mitochondrial biogenesis in brain subcortex by a neuronal nitric oxide synthase-dependent mechanism. AU - Gutsaeva,Diana R, AU - Carraway,Martha Sue, AU - Suliman,Hagir B, AU - Demchenko,Ivan T, AU - Shitara,Hiroshi, AU - Yonekawa,Hiromichi, AU - Piantadosi,Claude A, PY - 2008/2/29/pubmed PY - 2008/4/9/medline PY - 2008/2/29/entrez SP - 2015 EP - 24 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J. Neurosci. VL - 28 IS - 9 N2 - 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 PO2 responses to acute hypoxia among these strains of mice. In Wt mice, hypoxia increased mRNA levels for peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1 alpha), 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 in nNOS-/- mice was normal at baseline but did not respond to hypoxia. After hypoxia, subcortical mtDNA content increased in Wt and eNOS-/- mice but not in nNOS-/- mice. Hypoxia stimulated PGC-1alpha protein expression and phosphorylation of protein kinase A and cAMP response element binding (CREB) protein in Wt mice, but CREB only was activated in eNOS-/- mice and not in nNOS-/- mice. These findings demonstrate that hypoxic preconditioning elicits subcortical mitochondrial biogenesis by a novel mechanism that requires nNOS regulation of PGC-1alpha and CREB. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/18305236/Transient_hypoxia_stimulates_mitochondrial_biogenesis_in_brain_subcortex_by_a_neuronal_nitric_oxide_synthase_dependent_mechanism_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=18305236 DB - PRIME DP - Unbound Medicine ER -