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The Journal of Neuroscience, February 27, 2008, 28(9):2015-2024; doi:10.1523/JNEUROSCI.5654-07.2008

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Cellular/Molecular
Transient Hypoxia Stimulates Mitochondrial Biogenesis in Brain Subcortex by a Neuronal Nitric Oxide Synthase-Dependent Mechanism

Diana R. Gutsaeva,^1,2 * Martha Sue Carraway,^1 * Hagir B. Suliman,¹ Ivan T. Demchenko,^1,2 Hiroshi Shitara,³ Hiromichi Yonekawa,³ and Claude A. Piantadosi¹

¹Departments of Medicine, Anesthesiology, and Center for Hyperbaric Medicine and Environmental Physiology, Duke University Medical Center, Durham, North Carolina 27710, ²Institute of Evolutionary Physiology and Biochemistry RAS, St. Petersburg 197376, Russia, and ³Department of Laboratory Animal Science, Tokyo Metropolitan Institute of Medical Science, Tokyo 113 8613, Japan

Correspondence should be addressed to Dr. Claude A. Piantadosi, Duke University Medical Center, Box 3315, Durham, NC 27710. Email: piant001{at}mc.duke.edu

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- coactivator-1 (PGC-1 ), 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-1 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-1 and CREB.

Key words: mitochondria; nitric oxide; mitochondrial biogenesis; hypoxia; brain metabolism; energy metabolism

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Received June 29, 2007; accepted Dec. 27, 2007.

Correspondence should be addressed to Dr. Claude A. Piantadosi, Duke University Medical Center, Box 3315, Durham, NC 27710. Email: piant001{at}mc.duke.edu

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