MITOCHONDRIAL BIOGENESIS IN SEPSIS-INDUCED ORGAN DYSFUNCTION
A Claude
Duke Universitycity: Durham country: United States (us)
Grant 5R01GM084116-04 from National Institute Of General Medical Sciences
Abstract: We propose to investigate the importance of mitochondrial biogenesis in the evolution of organ dysfunction in sepsis. Multiple organ dysfunction syndrome (MODS) is a frequent complication of sepsis, and although sepsis mortality increases almost linearly with the number of organs involved, the underlying pathogenesis of organ failure and how it resolves are not understood. We have shown in animals with sepsis that damage to mitochondria in tissues contributes to abnormalities in cellular energy production and, when repair mechanisms fail, to cell death and organ dysfunction (6-12). This is balanced by mitochondrial biogenesis, the adaptive program that maintains the capacity for mitochondrial energy production through maintenance and repair of mitochondrial components and through synthesis of new organelles. We hypothesize that mitochondrial damage is an early finding in patients with severe sepsis and that the extent of mitochondrial injury predicts the severity of sepsis-induced MODS. We propose that the resolution of MODS in sepsis depends on the initiation of mitochondrial biogenesis. The mitochondrial genome is a particularly sensitive target for oxidative injury in sepsis because it is located close to the site of oxidative phosphorylation and is relatively unprotected by anti-oxidant defenses (13-15). Our preliminary data show that mitochondrial DNA (mtDNA) injury and biogenesis are an intrinsic part of the host response to severe infection. To determine how these relate to the development and resolution of MODS in patients, we propose the following Specific Aims Specific Aim 1. Determine if mitochondrial DNA damage in peripheral blood mononuclear cells (PBMC) predicts organ dysfunction in non-diabetic and diabetic septic patients, especially critical care myopathy. Specific Aim 2. Determine if activation of the molecular mechanisms of mitochondrial DNA replication and biogenesis in PBMC predicts recovery from sepsis-induced organ dysfunction. Specific Aim 3. Determine whether specific molecular pathways are critical to resolution of sepsis- induced organ injury in wild type and diabetic mice. We will characterize mitochondria in PBMC from septic patients to determine the relationship between mtDNA damage and biogenesis to disease severity and outcome. Using a clinically relevant animal model of sepsis, we will investigate pathways important for mitochondrial biogenesis and recovery of organ function and determine whether these are feasible targets for effecting recovery of MODS in septic patients. The results will provide a new approach to the clinical assessment of energy failure during sepsis, stratify patient risk for sepsis complications and use the results to enhance existing animal models, and identify patients who might benefit from therapeutic interventions that promote mitochondrial biogenesis. The multiple organ dysfunction syndrome (MODS) is a frequent complication of sepsis from severe infections, with ~750,000 reported cases per year and an overall mortality rate of about 30%. Mortality is directly related to severity of organ failure, but the underlying causes and what determines resolution are not understood. These studies will investigate the role of mitochondrial injury and biogenesis in the pathogenesis of organ dysfunction in sepsis, and should lead to new therapies to enhance recovery from organ failures in sepsis
Keywords: Animal Model; Animals; Antioxidants; Biogenesis; Biopsy; Case Study; Cell Death; Clinical assessments; clinically relevant; Complication; Critical Care; Critical Pathways; Data; Development; Diabetes Mellitus; diabetic; Diabetic mouse; Disease Outcome; DNA biosynthesis; DNA Damage; Elderly; Equilibrium; Evolution; Failure (biologic function); Functional disorder; Health; high risk; Homeostasis; Immune response; Infection; Injury; Lead; Maintenance; Measures; Metabolic; Mitochondria; Mitochondrial DNA; mitochondrial genome; Molecular; Mortality Vital Statistics; Multiple Organ Failure; Myopathy; non-diabetic; novel strategies; Organ; Organ failure; Organelles; oxidative damage; Oxidative Phosphorylation; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Production; programs; Recovery; Regulation; repaired; Resolution; restoration; Risk; Role; Sepsis; septic; Severities; Severity of illness; Signal Transduction; Site; Skeletal muscle structure; Therapeutic Intervention; Tissues
Relevance: The multiple organ dysfunction syndrome (MODS) is a frequent complication of sepsis from severe infections, with ~750,000 reported cases per year and an overall mortality rate of about 30%. Mortality is directly related to severity of organ failure, but the underlying causes and what determines resolution are not understood. These studies will investigate the role of mitochondrial injury and biogenesis in the pathogenesis of organ dysfunction in sepsis, and should lead to new therapies to enhance recovery from organ failures in sepsis
Project start date: 2009-04-01
Project end date: 2013-01-31
Budget start date: 1-FEB-2012
Budget end date: 31-JAN-2013
5R01GM084116-04 (2012): $316494
Sponsored Links Excellgen http://Excellgen.com
MITOCHONDRIAL BIOGENESIS IN SEPSIS-INDUCED ORGAN DYSFUNCTION
A Claude, Associate Professor
Duke Universitycity: Durham country: United States (us)
Grant 5R01GM084116-03 from National Institute Of General Medical Sciences
Abstract: We propose to investigate the importance of mitochondrial biogenesis in the evolution of organ dysfunction in sepsis. Multiple organ dysfunction syndrome (MODS) is a frequent complication of sepsis, and although sepsis mortality increases almost linearly with the number of organs involved, the underlying pathogenesis of organ failure and how it resolves are not understood. We have shown in animals with sepsis that damage to mitochondria in tissues contributes to abnormalities in cellular energy production and, when repair mechanisms fail, to cell death and organ dysfunction (6-12). This is balanced by mitochondrial biogenesis, the adaptive program that maintains the capacity for mitochondrial energy production through maintenance and repair of mitochondrial components and through synthesis of new organelles. We hypothesize that mitochondrial damage is an early finding in patients with severe sepsis and that the extent of mitochondrial injury predicts the severity of sepsis-induced MODS. We propose that the resolution of MODS in sepsis depends on the initiation of mitochondrial biogenesis. The mitochondrial genome is a particularly sensitive target for oxidative injury in sepsis because it is located close to the site of oxidative phosphorylation and is relatively unprotected by anti-oxidant defenses (13-15). Our preliminary data show that mitochondrial DNA (mtDNA) injury and biogenesis are an intrinsic part of the host response to severe infection. To determine how these relate to the development and resolution of MODS in patients, we propose the following Specific Aims Specific Aim 1. Determine if mitochondrial DNA damage in peripheral blood mononuclear cells (PBMC) predicts organ dysfunction in non-diabetic and diabetic septic patients, especially critical care myopathy. Specific Aim 2. Determine if activation of the molecular mechanisms of mitochondrial DNA replication and biogenesis in PBMC predicts recovery from sepsis-induced organ dysfunction. Specific Aim 3. Determine whether specific molecular pathways are critical to resolution of sepsis- induced organ injury in wild type and diabetic mice. We will characterize mitochondria in PBMC from septic patients to determine the relationship between mtDNA damage and biogenesis to disease severity and outcome. Using a clinically relevant animal model of sepsis, we will investigate pathways important for mitochondrial biogenesis and recovery of organ function and determine whether these are feasible targets for effecting recovery of MODS in septic patients. The results will provide a new approach to the clinical assessment of energy failure during sepsis, stratify patient risk for sepsis complications and use the results to enhance existing animal models, and identify patients who might benefit from therapeutic interventions that promote mitochondrial biogenesis. The multiple organ dysfunction syndrome (MODS) is a frequent complication of sepsis from severe infections, with ~750,000 reported cases per year and an overall mortality rate of about 30%. Mortality is directly related to severity of organ failure, but the underlying causes and what determines resolution are not understood. These studies will investigate the role of mitochondrial injury and biogenesis in the pathogenesis of organ dysfunction in sepsis, and should lead to new therapies to enhance recovery from organ failures in sepsis
Keywords: advanced age; Aged 65 and Over; Animal Model; Animal Models and Related Studies; Animals; anti-oxidant; Antioxidants; ATP biosynthesis (oxidative); Autoregulation; balance; balance function; Biogenesis; biological signal transduction; Biopsy; bloodstream infection; Body Tissues; case report; Case Study; Cell Communication and Signaling; Cell Death; Cell Signaling; Clinical assessments; clinical relevance; clinically relevant; Complication; Critical Care; Critical Paths; Critical Pathways; Data; Development; diabetes; Diabetes Mellitus; diabetic; Diabetic mouse; Disease Outcome; disease severity; Disorder of muscle, unspecified; DNA biosynthesis; DNA Damage; DNA Injury; DNA Replication; DNA Synthesis; DNA, Mitochondrial; Dysfunction; Elderly; Elderly, over 65; elders; Equilibrium; Evolution; failure; Failure (biologic function); FLR; Functional disorder; geriatric; Health; heavy metal lead; heavy metal Pb; high risk; Homeostasis; host response; Immune response; immunoresponse; Infection; Injury; intervention therapy; Intracellular Communication and Signaling; late life; later life; Lead; Maintenance; Maintenances; Measures; Metabolic; Mitochondria; mitochondrial; Mitochondrial DNA; mitochondrial genome; model organism; MOF syndrome; Molecular; Mortality; Mortality Vital Statistics; mouse model of diabetes; mtDNA; Multiple Organ Failure; multiple organ system failure; Muscle Disease; Muscle disease or syndrome; Muscle Disorders; Muscle, Skeletal; Muscle, Voluntary; Muscular Diseases; muscular disorder; Myopathic Conditions; Myopathic disease or syndrome; Myopathic Diseases and Syndromes; Myopathy; Myopathy, unspecified; necrocytosis; new approaches; non-diabetic; nondiabetic; novel approaches; novel strategies; novel strategy; older adult; older person; Organ; Organ Dysfunction Syndrome, Multiple; Organ failure; Organelles; Origin of Life; oxidative damage; Oxidative Phosphorylation; Oxidative Phosphorylation Pathway; Oxidative Stress; Pathogenesis; pathophysiology; pathway; Pathway interactions; Patients; Pb element; PBMC; Peripheral Blood Mononuclear Cell; Physiological Homeostasis; Physiopathology; Production; programs; Programs (PT); Programs [Publication Type]; Recovery; Regulation; repair; repaired; Resolution; restoration; Risk; Role; senior citizen; Sepsis; septic; Severities; Severity of illness; Signal Transduction; Signal Transduction Systems; Signaling; Site; Skeletal muscle structure; Skeletal Muscle Tissue; social role; Therapeutic Intervention; Tissues
Relevance: The multiple organ dysfunction syndrome (MODS) is a frequent complication of sepsis from severe infections, with ~750,000 reported cases per year and an overall mortality rate of about 30%. Mortality is directly related to severity of organ failure, but the underlying causes and what determines resolution are not understood. These studies will investigate the role of mitochondrial injury and biogenesis in the pathogenesis of organ dysfunction in sepsis, and should lead to new therapies to enhance recovery from organ failures in sepsis
Project start date: 2009-04-01
Project end date: 2013-01-31
Budget start date: 1-FEB-2011
Budget end date: 31-JAN-2012
PFA/PA: PA-07-233
5R01GM084116-03 (2011): $287722
Grants awarded to A Claude
REGULATION OF MITOCHONDRIAL BIOGENESIS BY HEME OXYGENASE-1
A Claude, Professor
Duke Universitycity: Durham country: United States (us)
Grant 5R01HL090679-04 from National Heart, Lung, And Blood Institute
Abstract: This is an amended application to study a novel function for the inducible enzyme that catalyzes heme degradation, heme oxygenase-1 (HO-1), in the regulation of mitochondrial biogenesis. The proposed mechanism is based on the endogenous production of CO by HO (HO/CO). CO, like nitric oxide (NO), is increasingly recognized as a gaseous signaling molecule serving regulatory roles in health and disease. We have discovered that CO at physiological concentrations up-regulates the nuclear transcription factors, nuclear respiratory factors (NRF) -1 and -2, and the central co-activator, PGC-11, which regulate , mitochondrial biogenesis. Our preliminary data show that CO promotes mtDNA replication and increases mtDNA copy number in the mouse heart during mitochondrial biogenesis. The latter is an essential process under nuclear control that requires mitochondrial fusion, fission, and respiratory protein synthesis in order to meet the organ´s continuous demand for aerobic ATP synthesis for contractile function. The pathways by which HO/CO promotes biogenesis are not yet well defined but we have new preliminary data implicating CO-cytochrome c oxidase a3-heme binding in mitochondria in the mechanism, leading to H2O2-mediated activation of the pro-survival kinase, Akt/PKB and nuclear translocation of the redox-sensitive Nrf2 transcription factor. Our hypothesis is that physiological (endogenous) CO produced by HO serves a cell survival function by redox activation of mitochondrial biogenesis to produce an anti-oxidant and anti- apoptotic mitochondrial phenotype. We propose three Specific Aims Aim 1 Test the hypothesis that exogenous and endogenous CO activates cardiac mitochondrial biogenesis through Akt-dependent phosphorylation of PGC-11. Aim 2 Test the hypothesis that mitochondrial H2O2 signaling by HO/CO and its interplay through the Nrf2 transcription factor regulate HO-1 and NRF-1 gene expression for the transcriptional regulation of mitochondrial biogenesis. Aim 3 Test the hypothesis that the myocardial protective effect of CO depends on endogenous HO-1 activity and the generation of an apoptosis-resistent mitochondrial phenotype in doxorubicin cardiomyopathy. The completion of these Aims will expand and develop our understanding of the role of CO as a cell-signaling molecule in mitochondrial health and disease. The implication is that HO/CO-regulated mitochondrial biogenesis is fundamental to the maintenance of normal cardiovascular function as well as to adaptation to oxidative stress and pathogenic inflammation. This would provide a unifying mechanism for the protective role of HO- 1 that may be amenable to therapeutic intervention by a range of unique and novel strategies. This is new proposal to study a novel function for heme oxygenase-1 (HO-1), one of two main isoforms of the enzyme that converts heme into biliverdin, Fe, and carbon monoxide (CO). Our preliminary data implicate HO-1, through the production of CO, as a regulator of mitochondrial biogenesis. Our work in the mouse heart and in cardiomyocytes suggests the hypothesis that HO/CO-regulated mitochondrial biogenesis is fundamental for adaptation to oxidative and inflammatory stress. A successful test of our hypothesis would establish a unifying mechanism for the diverse protective roles of HO-1 in health and disease
Keywords: Aerobic; Antioxidants; Apoptosis; Apoptotic; ATP Synthesis Pathway; base; Biliverdine; Binding (Molecular Function); Biogenesis; Carbon Monoxide; Carboxyhemoglobin; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular Physiology; cell motility; Cell Survival; Cyclic GMP; cytochrome c oxidase; Data; design; Disease; Doxorubicin; Elements; Enzymes; GA-binding protein transcription factor; Gene Expression; Gene Expression Regulation; Generations; Growth Factor; Guanylate Cyclase; Health; Heart; Heme; heme a3; Heme Oxygenase (Decyclizing); Hemeproteins; Hydrogen Peroxide; Hypoxia; Inflammation; Inflammatory; Maintenance; Mediating; meetings; Metabolism; Mitochondria; Mitochondrial DNA; Mus; Myocardial; Nitric Oxide; novel; novel strategies; novel therapeutic intervention; Nuclear; nuclear respiratory factor; Nuclear Translocation; Organ; Organelles; Oxidation-Reduction; Oxidative Stress; Oxygenases; Pathway interactions; Phenotype; Phosphorylation; Phosphotransferases; Physiological; Process; Production; protective effect; Protein Biosynthesis; protein function; Protein Isoforms; Protein-Serine-Threonine Kinases; Regulation; respiratory protein; Role; Signal Transduction; Signaling Molecule; Site; Stress; Testing; Therapeutic Intervention; Tissues; transcription factor; Transcriptional Regulation; Work
Project start date: 2008-07-14
Project end date: 2012-04-30
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
PFA/PA: PA-07-070
5R01HL090679-04 (2011): $390000
CARBON MONOXIDE AND MITOCHONDRIAL QUALITY CONTROL IN SEPSIS-INDUCED LUNG INJURY
A Claude, Professor
Brigham And Women´s Hospitalcity: Boston country: United States (us)
Abstract: Acute lung injury (ALI) and multiple organ dysfunction syndrome (MODS) is a major cause of sepsis-induced mortality in the ICU. Patients who initially survive may subsequently die with immune paralysis characterized by poorly understood mechanisms involving the over-expression of counter-regulatory cytokines that suppress NF-KB-dependent pro-Inflammatory cytokine synthesis. Sepsis induces heme oxygenase-1 (HO-1; Hmox1), which has specific anti-inflammatory effects, e.g. via carbon monoxide (CO) mediated IL-10 producfion, and exerts powerful control over the transcriptional network of mitochondrial biogenesis, which safeguards energy metabolism by improving mitochondrial mass and promoting clearance of damaged organelles {mitophagy). Our preliminary data demonstrate that HO-1/CO up-regulates the suppressor of cytokine signaling-3 (S0CS3), the inflammasome inhibitor/anti-apoptotic protein BCIXL, DNA damage regulated autophagy modulator protein 1 (Drami), and the mitophagy genes NIX and BNIP3. This information suggests that the H0-1/C0 system links mitochondrial biogenesis, mitophagy, and counter inflammation through mechanisms involving S0CS3, BCIXL and Drami. We hypothesize that the transcriptional network of mitochondrial biogenesis regulates the anti-inflammatory response through HO-1/CO-dependent NFE2I2 and NRF-1 activation, leading to up-regulation of IL10 and S0CS3, activation of mitophagy. and suppression of inflammasome-mediated IL-1 B production and suppression of apoptosis. Using Staphylococcal aureus (S. aureus) sepsis and pneumonia in mice and relevant cell models in two mechanistic molecular Aims, and through a translafional third Aim, we will address how this integrated process of mitochondrial quality control mitigates lung and liver inflammation and hastens the resolution of sepsis. Completion of these Aims and a successful test of this hypothesis would allow a paradigm shift in our understanding and approach to sepsis-induced organ failure both experimentally and clinically, as well as test CO pre-clinically as a way to improve mitochondrial quality control in ALI and MODS
Keywords: Address; Anti-inflammatory; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Apoptotic; Autophagocytosis; Binding (Molecular Function); Biogenesis; Biopsy; BNIP3L gene; Carbon Monoxide; Cause of Death; Cell Death; Cell model; Critical Illness; cytokine; Cytokine Inducible SH2-Containing Protein; Data; DNA Damage; Effector Cell; Energy Metabolism; Experimental Models; Gene Expression; Gene Expression Regulation; Genes; Genomics; Heme; Heme Oxygenase (Decyclizing); Hepatic; Hepatocyte; HOI; Human; IL8 gene; Immune; Immune system; Immunity; improved; Inflammation; Inflammatory; Inflammatory Response; inhibitor/antagonist; Instruction; Interleukin-1; Interleukin-10; Interleukin-18; Link; Liver; loss of function; Lung; Lung Inflammation; lung injury; Lung Injury, Acute; Mediating; Mediator of activation protein; Mitochondria; Modeling; Molecular; Mortality Vital Statistics; mRNA Expression; Multiple Organ Failure; Mus; Natural immunosuppression; novel; novel therapeutics; nuclear respiratory factor; Organ; Organ failure; Organelles; Oxidation-Reduction; Paralysed; Patients; Peripheral Blood Mononuclear Cell; Plasma; Pneumonia; prevent; Process; Production; programs; Promotor (Genetics); protein phosphatase inhibitor-2; Proteins; Protocols documentation; Quality Control; receptor; Regulation; Resolution; Response Elements; Sepsis; Signal Transduction; Skeletal muscle structure; Stress; System; Testing; Therapeutic; TNF gene; transcription factor; Translations; Up-Regulation (Physiology); Work
Relevance: RELEVANCE (See instructions): Acute lung injury (ALI) and multiple organ dysfunction syndrome (MODS) in sepsis is a major cause of death in ICU patients. Patients who initially survive may subsequently die with so-called "immune paralysis," which is poorly understood. The induction of heme oxygenase-1 (HO-1; Hmox1) and endogenous CO production has powerful anti-inflammatory effects and exerts control over mitochondrial biogenesis, which improves mitochondrial mass and promotes the clearance of damaged organelles (mitophagy). We propose that gene regulation for mitochondrial biogenesis cross-talks with the anti-Inflammatory response through HO-1/CO, increasing the expression of anti-inflammatory IL10 and S0CS3, activating mitophagy and preventing cell death. Using experimental models of S. aureus pneumonia and sepsis, we will address how this integrated process of mitochondrial quality control mitigates inflammation in the lungs and liver and hastens the resolution of sepsis, thereby greatly improving our understanding and approach to sepsis-induced MODS
Budget start date: 15-AUG-2011
Budget end date: 30-JUN-2012
PFA/PA: PAR-09-185
1P01HL108801-01_5936 (2011): $503164