This is an amended application to study the basic mechanisms of action of nitric oxide (NO) in mitochondrial biogenesis in the liver in sepsis. NO synthase induction is fundamental to the sepsis-induced immune response but the production reactive nitrogen and oxygen species (RNS, ROS) is a stress that drives mitochondrial dysfunction and is important in the pathogenesis of multiple organ failure (MOF). We have discovered that RNS and ROS production in experimental sepsis damage mitochondrial DNA (mtDNA), thereby impairing mitochondrial transcription, proteome fidelity, and mitochondrial function. This mitochondrial damage stimulates cellular compensation involvingmitochondrialbiogenesis, which requires activation ofmitochondrial transcription factor A (mtTFA) and two nuclear transcription factors, nuclear respiratory factor-1 and -2 (NRF-1 and -2),and a co-activator, PGC-1. These unique cell responses, under nuclear control, signify a crucial side of mitochondrial biology modulated by RNS and ROS, and one that is pro-survival. Though we still know very little about regulation of biogenesis in inflammation or its disruption in sepsis, our data show clearly that mitochondrial pathology is not limited simply to the NO-chemistry that damages mitochondria and kills cells. Therefore, we propose to test the hypothesis that iNOS-stimulated mitochondrial biogenesis opposes cell necrosis in sepsis, and thereby, regulation of biogenesis is an important determinant of cell survival. To test this hypothesis we propose three Specific Aims:
Aim 1 : Measure the contribution of iNOS to the pathogenesis of damage to hepatic mitochondrial DNA and proteins in sepsis using wild type and iNOS knockout mice;
Aim 2 : Define the importance of iNOS in mitochondrial transcription factor A (Tfam) activation and the restoration of hepatic mtDNA copy number and transcription in wild type and iNOS knockout mice in sepsis;
Aim 3 : Determine the contribution of iNOS to nuclear transcriptional activation of biogenesis in sepsis via NRF-1 and NRF-2 expression in wild type and iNOS knockout mice. This work will provide a better mechanistic understanding of the nuclear-mitochondrial communication during the host inflammatory response, which should help foster new molecular strategies to assess the ability of mitochondrial response markers to predict MOF and to guide interventions to prevent and eventually to treat sepsis-induced MOF.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI064789-05
Application #
7743390
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Minnicozzi, Michael
Project Start
2005-12-15
Project End
2010-11-30
Budget Start
2009-12-01
Budget End
2010-11-30
Support Year
5
Fiscal Year
2010
Total Cost
$257,445
Indirect Cost
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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Demchenko, Ivan T; Moskvin, Alexander N; Krivchenko, Alexander I et al. (2012) Nitric oxide-mediated central sympathetic excitation promotes CNS and pulmonary Oýýý toxicity. J Appl Physiol 112:1814-23
Piantadosi, Claude A (2012) Regulation of mitochondrial processes by protein S-nitrosylation. Biochim Biophys Acta 1820:712-21
Piantadosi, Claude A; Withers, Crystal M; Bartz, Raquel R et al. (2011) Heme oxygenase-1 couples activation of mitochondrial biogenesis to anti-inflammatory cytokine expression. J Biol Chem 286:16374-85
Demchenko, Ivan T; Zhilyaev, S Yu; Moskvin, A N et al. (2011) Autonomic activation links CNS oxygen toxicity to acute cardiogenic pulmonary injury. Am J Physiol Lung Cell Mol Physiol 300:L102-11
Sweeney, Timothy E; Suliman, Hagir B; Hollingsworth, John W et al. (2010) Differential regulation of the PGC family of genes in a mouse model of Staphylococcus aureus sepsis. PLoS One 5:e11606
Li, Zhuowei; Potts, Erin N; Piantadosi, Claude A et al. (2010) Hyaluronan fragments contribute to the ozone-primed immune response to lipopolysaccharide. J Immunol 185:6891-8
Carraway, Martha S; Suliman, Hagir B; Jones, W Schuyler et al. (2010) Erythropoietin activates mitochondrial biogenesis and couples red cell mass to mitochondrial mass in the heart. Circ Res 106:1722-30
Suliman, Hagir B; Babiker, Abdelwahid; Withers, Crystal M et al. (2010) Nitric oxide synthase-2 regulates mitochondrial Hsp60 chaperone function during bacterial peritonitis in mice. Free Radic Biol Med 48:736-46
Reynolds, Crystal M; Suliman, Hagir B; Hollingsworth, John W et al. (2009) Nitric oxide synthase-2 induction optimizes cardiac mitochondrial biogenesis after endotoxemia. Free Radic Biol Med 46:564-72

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