Transient hypoxia stimulates mitochondrial biogenesis in brain subcortex by a neuronal nitric oxide synthase-dependent mechanism.
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.
Gutsaeva
Diana R
DR
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
Carraway
Martha Sue
MS
Suliman
Hagir B
HB
Demchenko
Ivan T
IT
Shitara
Hiroshi
H
Yonekawa
Hiromichi
H
Piantadosi
Claude A
CA
D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000473:pathology / Q000503:physiopathology / Q000648:ultrastructure*; D050882:CREB-Binding Protein / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000502:physiology*; D004791:Enzyme Inhibitors; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000096:biosynthesis; D000860:Hypoxia / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D052248:Nitric Oxide Synthase Type I / Q000172:deficiency*; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency; D052250:Nitric Oxide Synthase Type III; D009687:Nuclear Proteins / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors
D004272:DNA, Mitochondrial; D004791:Enzyme Inhibitors; D009687:Nuclear Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496321:Nos1 protein, mouse; C496315:Nos3 protein, mouse; D050882:CREB-Binding Protein; D019331:NG-Nitroarginine Methyl Ester