Browsing by Author "Suliman, Hagir B"

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    Co-regulation of nuclear respiratory factor-1 by NFkappaB and CREB links LPS-induced inflammation to mitochondrial biogenesis.
    (J Cell Sci, 2010-08-01) Suliman, Hagir B; Sweeney, Timothy E; Withers, Crystal M; Piantadosi, Claude A
    The nuclear respiratory factor-1 (NRF1) gene is activated by lipopolysaccharide (LPS), which might reflect TLR4-mediated mitigation of cellular inflammatory damage via initiation of mitochondrial biogenesis. To test this hypothesis, we examined NRF1 promoter regulation by NFκB, and identified interspecies-conserved κB-responsive promoter and intronic elements in the NRF1 locus. In mice, activation of Nrf1 and its downstream target, Tfam, by Escherichia coli was contingent on NFκB, and in LPS-treated hepatocytes, NFκB served as an NRF1 enhancer element in conjunction with NFκB promoter binding. Unexpectedly, optimal NRF1 promoter activity after LPS also required binding by the energy-state-dependent transcription factor CREB. EMSA and ChIP assays confirmed p65 and CREB binding to the NRF1 promoter and p65 binding to intron 1. Functionality for both transcription factors was validated by gene-knockdown studies. LPS regulation of NRF1 led to mtDNA-encoded gene expression and expansion of mtDNA copy number. In cells expressing plasmid constructs containing the NRF-1 promoter and GFP, LPS-dependent reporter activity was abolished by cis-acting κB-element mutations, and nuclear accumulation of NFκB and CREB demonstrated dependence on mitochondrial H(2)O(2). These findings indicate that TLR4-dependent NFκB and CREB activation co-regulate the NRF1 promoter with NFκB intronic enhancement and redox-regulated nuclear translocation, leading to downstream target-gene expression, and identify NRF-1 as an early-phase component of the host antibacterial defenses.
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    De novo Blood Biomarkers in Autism: Autoantibodies against Neuronal and Glial Proteins.
    (Behavioral sciences (Basel, Switzerland), 2019-04-29) Abou-Donia, Mohamed B; Suliman, Hagir B; Siniscalco, Dario; Antonucci, Nicola; ElKafrawy, Passent
    Autism spectrum disorders (ASDs) are the most common neurodevelopmental disorders with unidentified etiology. The behavioral manifestations of ASD may be a consequence of genetic and/or environmental pathology in neurodevelopmental processes. In this limited study, we assayed autoantibodies to a panel of vital neuronal and glial proteins in the sera of 40 subjects (10 children with ASD and their mothers along with 10 healthy controls, age-matched children and their mothers). Serum samples were screened using Western Blot analysis to measure immunoglobulin (IgG) reactivity against a panel of 9 neuronal proteins commonly associated with neuronal degeneration: neurofilament triplet proteins (NFP), tubulin, microtubule-associated proteins (tau), microtubule-associated protein-2 (MAP-2), myelin basic protein (MBP), myelin-associated glycoprotein (MAG), α-synuclein (SNCA) and astrocytes proteins such as glial fibrillary acidic protein (GFAP) and S100B protein. Our data show that the levels of circulating IgG class autoantibodies against the nine proteins were significantly elevated in ASD children. Mothers of ASD children exhibited increased levels of autoantibodies against all panel of tested proteins except for S100B and tubulin compared to age-matched healthy control children and their mothers. Control children and their mothers showed low and insignificant levels of autoantibodies to neuronal and glial proteins. These results strongly support the importance of anti-neuronal and glial protein autoantibodies biomarker in screening for ASD children and further confirm the importance of the involvement of the maternal immune system as an index that should be considered in fetal in utero environmental exposures. More studies are needed using larger cohort to verify these results and understand the importance of the presence of such autoantibodies in children with autism and their mothers, both as biomarkers and their role in the mechanism of action of autism and perhaps in its treatment.
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    Effects of high-intensity interval training with hyperbaric oxygen.
    (Frontiers in physiology, 2022-01) Alvarez Villela, Miguel; Dunworth, Sophia A; Kraft, Bryan D; Harlan, Nicole P; Natoli, Michael J; Suliman, Hagir B; Moon, Richard E
    Hyperbaric Oxygen (HBO2) has been proposed as a pre-conditioning method to enhance exercise performance. Most prior studies testing this effect have been limited by inadequate methodologies. Its potential efficacy and mechanism of action remain unknown. We hypothesized that HBO2 could enhance aerobic capacity by inducing mitochondrial biogenesis via redox signaling in skeletal muscle. HBO2 was administered in combination with high-intensity interval training (HIIT), a potent redox stimulus known to induce mitochondrial biogenesis. Aerobic capacity was tested during acute hypobaric hypoxia seeking to shift the limiting site of whole body V̇O2 from convection to diffusion, more closely isolating any effect of improved oxidative capacity. Healthy volunteers were screened with sea-level (SL) V̇O2peak testing. Seventeen subjects were enrolled (10 men, 7 women, ages 26.5±1.3 years, BMI 24.6±0.6 kg m-2, V̇O2peak SL = 43.4±2.1). Each completed 6 HIIT sessions over 2 weeks randomized to breathing normobaric air, "HIIT+Air" (PiO2 = 0.21 ATM) or HBO2 (PiO2 = 1.4 ATM) during training, "HIIT+HBO2" group. Training workloads were individualized based on V̇O2peak SL test. Vastus Lateralis (VL) muscle biopsies were performed before and after HIIT in both groups. Baseline and post-training V̇O2peak tests were conducted in a hypobaric chamber at PiO2 = 0.12 ATM. HIIT significantly increased V̇O2peak in both groups: HIIT+HBO2 31.4±1.5 to 35.2±1.2 ml kg-1·min-1 and HIIT+Air 29.0±3.1 to 33.2±2.5 ml kg-1·min-1 (p = 0.005) without an additional effect of HBO2 (p = 0.9 for interaction of HIIT x HBO2). Subjects randomized to HIIT+HBO2 displayed higher skeletal muscle mRNA levels of PPARGC1A, a regulator of mitochondrial biogenesis, and HK2 and SLC2A4, regulators of glucose utilization and storage. All other tested markers of mitochondrial biogenesis showed no additional effect of HBO2 to HIIT. When combined with HIIT, short-term modest HBO2 (1.4 ATA) has does not increase whole-body V̇O2peak during acute hypobaric hypoxia. (ClinicalTrials.gov Identifier: NCT02356900; https://clinicaltrials.gov/ct2/show/NCT02356900).
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    GAT inhibition preserves cerebral blood flow and reduces oxidant damage to mitochondria in rodents exposed to extreme hyperbaric oxygen.
    (Frontiers in molecular neuroscience, 2022-01) Demchenko, Ivan T; Suliman, Hagir B; Zhilyaey, Sergey Y; Alekseeva, Olga S; Platonova, Tatyana F; Makowski, Matthew S; Piantadosi, Claude A; Gasier, Heath G
    Oxygen breathing at elevated partial pressures (PO2's) at or more than 3 atmospheres absolute (ATA) causes a reduction in brain γ-aminobutyric acid (GABA) levels that impacts the development of central nervous system oxygen toxicity (CNS-OT). Drugs that increase brain GABA content delay the onset of CNS-OT, but it is unknown if oxidant damage is lessened because brain tissue PO2 remains elevated during hyperbaric oxygen (HBO2) exposures. Experiments were performed in rats and mice to measure brain GABA levels with or without GABA transporter inhibitors (GATs) and its influence on cerebral blood flow, oxidant damage, and aspects of mitochondrial quality control signaling (mitophagy and biogenesis). In rats pretreated with tiagabine (GAT1 inhibitor), the tachycardia, secondary rise in mean arterial blood pressure, and cerebral hyperemia were prevented during HBO2 at 5 and 6 ATA. Tiagabine and the nonselective GAT inhibitor nipecotic acid similarly extended HBO2 seizure latencies. In mice pretreated with tiagabine and exposed to HBO2 at 5 ATA, nuclear and mitochondrial DNA oxidation and astrocytosis was attenuated in the cerebellum and hippocampus. Less oxidant injury in these regions was accompanied by reduced conjugated microtubule-associated protein 1A/1B-light chain 3 (LC3-II), an index of mitophagy, and phosphorylated cAMP response element binding protein (pCREB), an initiator of mitochondrial biogenesis. We conclude that GABA prevents cerebral hyperemia and delays neuroexcitation under extreme HBO2, limiting oxidant damage in the cerebellum and hippocampus, and likely lowering mitophagy flux and initiation of pCREB-initiated mitochondrial biogenesis.
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    Heme oxygenase-1 regulates mitochondrial quality control in the heart.
    (JCI Insight, 2017-04-12) Hull, Travis D; Boddu, Ravindra; Guo, Lingling; Tisher, Cornelia C; Traylor, Amie M; Patel, Bindiya; Joseph, Reny; Prabhu, Sumanth D; Suliman, Hagir B; Piantadosi, Claude A; Agarwal, Anupam; George, James F
    The cardioprotective inducible enzyme heme oxygenase-1 (HO-1) degrades prooxidant heme into equimolar quantities of carbon monoxide, biliverdin, and iron. We hypothesized that HO-1 mediates cardiac protection, at least in part, by regulating mitochondrial quality control. We treated WT and HO-1 transgenic mice with the known mitochondrial toxin, doxorubicin (DOX). Relative to WT mice, mice globally overexpressing human HO-1 were protected from DOX-induced dilated cardiomyopathy, cardiac cytoarchitectural derangement, and infiltration of CD11b+ mononuclear phagocytes. Cardiac-specific overexpression of HO-1 ameliorated DOX-mediated dilation of the sarcoplasmic reticulum as well as mitochondrial disorganization in the form of mitochondrial fragmentation and increased numbers of damaged mitochondria in autophagic vacuoles. HO-1 overexpression promotes mitochondrial biogenesis by upregulating protein expression of NRF1, PGC1α, and TFAM, which was inhibited in WT animals treated with DOX. Concomitantly, HO-1 overexpression inhibited the upregulation of the mitochondrial fission mediator Fis1 and resulted in increased expression of the fusion mediators, Mfn1 and Mfn2. It also prevented dynamic changes in the levels of key mediators of the mitophagy pathway, PINK1 and parkin. Therefore, these findings suggest that HO-1 has a novel role in protecting the heart from oxidative injury by regulating mitochondrial quality control.
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    Heme Oxygenase-1/Carbon Monoxide System and Embryonic Stem Cell Differentiation and Maturation into Cardiomyocytes.
    (Antioxid Redox Signal, 2016-03-01) Suliman, Hagir B; Zobi, Fabio; Piantadosi, Claude A
    AIMS: The differentiation of embryonic stem (ES) cells into energetically efficient cardiomyocytes contributes to functional cardiac repair and is envisioned to ameliorate progressive degenerative cardiac diseases. Advanced cell maturation strategies are therefore needed to create abundant mature cardiomyocytes. In this study, we tested whether the redox-sensitive heme oxygenase-1/carbon monoxide (HO-1/CO) system, operating through mitochondrial biogenesis, acts as a mechanism for ES cell differentiation and cardiomyocyte maturation. RESULTS: Manipulation of HO-1/CO to enhance mitochondrial biogenesis demonstrates a direct pathway to ES cell differentiation and maturation into beating cardiomyocytes that express adult structural markers. Targeted HO-1/CO interventions up- and downregulate specific cardiogenic transcription factors, transcription factor Gata4, homeobox protein Nkx-2.5, heart- and neural crest derivatives-expressed protein 1, and MEF2C. HO-1/CO overexpression increases cardiac gene expression for myosin regulatory light chain 2, atrial isoform, MLC2v, ANP, MHC-β, and sarcomere α-actinin and the major mitochondrial fusion regulators, mitofusin 2 and MICOS complex subunit Mic60. This promotes structural mitochondrial network expansion and maturation, thereby supporting energy provision for beating embryoid bodies. These effects are prevented by silencing HO-1 and by mitochondrial reactive oxygen species scavenging, while disruption of mitochondrial biogenesis and mitochondrial DNA depletion by loss of mitochondrial transcription factor A compromise infrastructure. This leads to failure of cardiomyocyte differentiation and maturation and contractile dysfunction. INNOVATION: The capacity to augment cardiomyogenesis via a defined mitochondrial pathway has unique therapeutic potential for targeting ES cell maturation in cardiac disease. CONCLUSION: Our findings establish the HO-1/CO system and redox regulation of mitochondrial biogenesis as essential factors in ES cell differentiation as well as in the subsequent maturation of these cells into functional cardiac cells.
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    Mitochondrial Quality Control as a Therapeutic Target.
    (Pharmacol Rev, 2016-01) Suliman, Hagir B; Piantadosi, Claude A
    In addition to oxidative phosphorylation (OXPHOS), mitochondria perform other functions such as heme biosynthesis and oxygen sensing and mediate calcium homeostasis, cell growth, and cell death. They participate in cell communication and regulation of inflammation and are important considerations in aging, drug toxicity, and pathogenesis. The cell's capacity to maintain its mitochondria involves intramitochondrial processes, such as heme and protein turnover, and those involving entire organelles, such as fusion, fission, selective mitochondrial macroautophagy (mitophagy), and mitochondrial biogenesis. The integration of these processes exemplifies mitochondrial quality control (QC), which is also important in cellular disorders ranging from primary mitochondrial genetic diseases to those that involve mitochondria secondarily, such as neurodegenerative, cardiovascular, inflammatory, and metabolic syndromes. Consequently, mitochondrial biology represents a potentially useful, but relatively unexploited area of therapeutic innovation. In patients with genetic OXPHOS disorders, the largest group of inborn errors of metabolism, effective therapies, apart from symptomatic and nutritional measures, are largely lacking. Moreover, the genetic and biochemical heterogeneity of these states is remarkably similar to those of certain acquired diseases characterized by metabolic and oxidative stress and displaying wide variability. This biologic variability reflects cell-specific and repair processes that complicate rational pharmacological approaches to both primary and secondary mitochondrial disorders. However, emerging concepts of mitochondrial turnover and dynamics along with new mitochondrial disease models are providing opportunities to develop and evaluate mitochondrial QC-based therapies. The goals of such therapies extend beyond amelioration of energy insufficiency and tissue loss and entail cell repair, cell replacement, and the prevention of fibrosis. This review summarizes current concepts of mitochondria as disease elements and outlines novel strategies to address mitochondrial dysfunction through the stimulation of mitochondrial biogenesis and quality control.
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    Redox mechanisms of cardiomyocyte mitochondrial protection.
    (Front Physiol, 2015) Bartz, Raquel R; Suliman, Hagir B; Piantadosi, Claude A
    Oxidative and nitrosative stress are primary contributors to the loss of myocardial tissue in insults ranging from ischemia/reperfusion injury from coronary artery disease and heart transplantation to sepsis-induced myocardial dysfunction and drug-induced myocardial damage. This cell damage caused by oxidative and nitrosative stress leads to mitochondrial protein, DNA, and lipid modifications, which inhibits energy production and contractile function, potentially leading to cell necrosis and/or apoptosis. However, cardiomyocytes have evolved an elegant set of redox-sensitive mechanisms that respond to and contain oxidative and nitrosative damage. These responses include the rapid induction of antioxidant enzymes, mitochondrial DNA repair mechanisms, selective mitochondrial autophagy (mitophagy), and mitochondrial biogenesis. Coordinated cytoplasmic to nuclear cell-signaling and mitochondrial transcriptional responses to the presence of elevated cytoplasmic oxidant production, e.g., H2O2, allows nuclear translocation of the Nfe2l2 transcription factor and up-regulation of downstream cytoprotective genes such as heme oxygenase-1 which generates physiologic signals, such as CO that up-regulates Nfe212 gene transcription. Simultaneously, a number of other DNA binding transcription factors are expressed and/or activated under redox control, such as Nuclear Respiratory Factor-1 (NRF-1), and lead to the induction of genes involved in both intracellular and mitochondria-specific repair mechanisms. The same insults, particularly those related to vascular stress and inflammation also produce elevated levels of nitric oxide, which also has mitochondrial protein thiol-protective functions and induces mitochondrial biogenesis through cyclic GMP-dependent and perhaps other pathways. This brief review provides an overview of these pathways and interconnected cardiac repair mechanisms.
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    Skeletal muscle mitochondrial fragmentation and impaired bioenergetics from nutrient overload are prevented by carbon monoxide.
    (American journal of physiology. Cell physiology, 2020-10) Gasier, Heath G; Dohl, Jacob; Suliman, Hagir B; Piantadosi, Claude A; Yu, Tianzheng
    Nutrient excess increases skeletal muscle oxidant production and mitochondrial fragmentation that may result in impaired mitochondrial function, a hallmark of skeletal muscle insulin resistance. This led us to explore whether an endogenous gas molecule, carbon monoxide (CO), which is thought to prevent weight gain and metabolic dysfunction in mice consuming high-fat diets, alters mitochondrial morphology and respiration in C2C12 myoblasts exposed to high glucose (15.6 mM) and high fat (250 µM BSA-palmitate) (HGHF). Also, skeletal muscle mitochondrial morphology, distribution, respiration, and energy expenditure were examined in obese resistant (OR) and obese prone (OP) rats that consumed a high-fat and high-sucrose diet for 10 wk with or without intermittent low-dose inhaled CO and/or exercise training. In cells exposed to HGHF, superoxide production, mitochondrial membrane potential (ΔΨm), mitochondrial fission regulatory protein dynamin-related protein 1 (Drp1) and mitochondrial fragmentation increased, while mitochondrial respiratory capacity was reduced. CO decreased HGHF-induced superoxide production, Drp1 protein levels and mitochondrial fragmentation, maintained ΔΨm, and increased mitochondrial respiratory capacity. In comparison with lean OR rats, OP rats had smaller skeletal muscle mitochondria that contained disorganized cristae, a normal mitochondrial distribution, but reduced citrate synthase protein expression, normal respiratory responses, and a lower energy expenditure. The combination of inhaled CO and exercise produced the greatest effect on mitochondrial morphology, increasing ADP-stimulated respiration in the presence of pyruvate, and preventing a decline in resting energy expenditure. These data support a therapeutic role for CO and exercise in preserving mitochondrial morphology and respiration during metabolic overload.
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    The CO/HO system reverses inhibition of mitochondrial biogenesis and prevents murine doxorubicin cardiomyopathy.
    (J Clin Invest, 2007-12) Suliman, Hagir B; Carraway, Martha Sue; Ali, Abdelwahid S; Reynolds, Chrystal M; Welty-Wolf, Karen E; Piantadosi, Claude A
    The clinical utility of anthracycline anticancer agents, especially doxorubicin, is limited by a progressive toxic cardiomyopathy linked to mitochondrial damage and cardiomyocyte apoptosis. Here we demonstrate that the post-doxorubicin mouse heart fails to upregulate the nuclear program for mitochondrial biogenesis and its associated intrinsic antiapoptosis proteins, leading to severe mitochondrial DNA (mtDNA) depletion, sarcomere destruction, apoptosis, necrosis, and excessive wall stress and fibrosis. Furthermore, we exploited recent evidence that mitochondrial biogenesis is regulated by the CO/heme oxygenase (CO/HO) system to ameliorate doxorubicin cardiomyopathy in mice. We found that the myocardial pathology was averted by periodic CO inhalation, which restored mitochondrial biogenesis and circumvented intrinsic apoptosis through caspase-3 and apoptosis-inducing factor. Moreover, CO simultaneously reversed doxorubicin-induced loss of DNA binding by GATA-4 and restored critical sarcomeric proteins. In isolated rat cardiac cells, HO-1 enzyme overexpression prevented doxorubicin-induced mtDNA depletion and apoptosis via activation of Akt1/PKB and guanylate cyclase, while HO-1 gene silencing exacerbated doxorubicin-induced mtDNA depletion and apoptosis. Thus doxorubicin disrupts cardiac mitochondrial biogenesis, which promotes intrinsic apoptosis, while CO/HO promotes mitochondrial biogenesis and opposes apoptosis, forestalling fibrosis and cardiomyopathy. These findings imply that the therapeutic index of anthracycline cancer chemotherapeutics can be improved by the protection of cardiac mitochondrial biogenesis.
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    The HO-1/CO System and Mitochondrial Quality Control in Skeletal Muscle.
    (Exercise and sport sciences reviews, 2021-10-22) Gasier, Heath G; Suliman, Hagir B; Piantadosi, Claude A

    Abstract

    Inducible heme oxygenase (HO)-1 catalyzes the breakdown of heme to biliverdin, iron and carbon monoxide (CO). CO binds to cytochrome c oxidase and alters mitochondrial redox balance and coordinately regulates mitochondrial quality control (MQC) during oxidant stress and inflammation. The hypothesis presented is that skeletal muscle HO-1/CO system helps modulate components in the MQC cycle during metabolic stress.