Abstract 306: DJ-1 Preserves Mitochondrial Function in the Ischemic Heart by Reducing the Glycation of Complex I

2019 ◽  
Vol 125 (Suppl_1) ◽  
Author(s):  
Yvanna Pantner ◽  
Yuuki Shimizu ◽  
Rohini Polavarapu ◽  
Lian Li ◽  
Lih-Shen Chin ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Complex I ◽  
Ischemic Heart

Ageing-induced decrease in cardiac mitochondrial function in healthy rats

2013 ◽  
Vol 91 (8) ◽  
pp. 593-600 ◽  
Author(s):  
Oana M. Duicu ◽  
Silvia N. Mirica ◽  
Dorina E. Gheorgheosu ◽  
Andreea I. Privistirescu ◽  
Ovidiu Fira-Mladinescu ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Complex I ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Heart Mitochondria ◽  
Ros Production ◽  
Sprague Dawley ◽  
Retention Capacity ◽  
Mptp Opening ◽  
Sprague Dawley Rats

It is widely recognized that mitochondrial dysfunction is a key component of the multifactorial process of ageing. The effects of age on individual components of mitochondrial function vary across species and strains. In this study we investigated the oxygen consumption, the mitochondrial membrane potential (Δψ), the sensitivity of mitochondrial permeability transition pore (mPTP) to calcium overload, and the production of reactive oxygen species (ROS) in heart mitochondria isolated from old compared with adult healthy Sprague–Dawley rats. Respirometry studies and Δψ measurements were performed with an Oxygraph-2k equipped with a tetraphenylphosphonium electrode. ROS production and calcium retention capacity were measured spectrofluorimetrically. Our results show an important decline for all bioenergetic parameters for both complex I and complex II supported-respiration, a decreased Δψ in mitochondria energized with complex I substrates, and an increased mitochondrial ROS production in the old compared with the adult group. Mitochondrial sensitivity to Ca2+-induced mPTP opening was also increased in the old compared with the adult animals. Moreover, the protective effect of cyclosporine A on mPTP opening was significantly reduced in the old group. We conclude that healthy ageing is associated with a decrease in heart mitochondria function in Sprague–Dawley rats.

Abstract 355: Effect of Poloxamer 188 on Rat Brain Isolated Mitochondria After Exposure to Hydrogen Peroxide

Circulation ◽  
2019 ◽  
Vol 140 (Suppl_2) ◽  
Author(s):  
Johannes A Pille ◽  
Michele M Salzman ◽  
Anna A Sonju ◽  
Felicia P Lotze ◽  
Josephine E Hees ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Oxygen Consumption ◽  
Mitochondrial Function ◽  
Complex I ◽  
Room Temperature ◽  
In Vitro Model ◽  
Atp Synthesis ◽  
Complex Ii ◽  
Vitro Model

Introduction: In a pig model of myocardial infarction (MI), intracoronary delivered Poloxamer (P) 188 significantly reduces ischemia/reperfusion (IR) injury when given immediately upon reperfusion, with improved mitochondrial function as a predominant effect. As mitochondria are heavily damaged during IR, a direct effect of P188 on mitochondria may lead to better therapy options during reperfusion. To show not only a similar reduction of IR injury by P188 in the brain, but also a direct P188 effect on mitochondria, we established an in-vitro model of IR that consists of damaging isolated rat brain mitochondria with hydrogen peroxide (H 2 O 2 ), one component of ischemia, then applying P188, and analyzing mitochondrial function. Methods: Male Sprague-Dawley rat brains were removed, and the mitochondria isolated by differential centrifugation and Percoll gradients, then kept on ice to slow their bioenergetics prior to any experimental treatments. Mitochondria were exposed to 200 μM H 2 O 2 for 10 min at room temperature with slight agitation; controls received no H 2 O 2 . Samples were then diluted ½ with buffer ± P188 (250 μM after dilution) to simulate reperfusion and treatment, and kept at room temperature for 10 further minutes. ATP synthesis was measured in a luminometer using a luciferase enzymatic assay. Oxygen consumption was measured by closed cell respirometry with an oxygen meter. In both assays, Complex I and Complex II were examined; Complex I substrates glutamate and malate, Complex II substrate succinate plus the Complex I inhibitor rotenone. Statistics: Data are expressed as mean ± SEM. One-Way ANOVA, SNK-Test; Kruskal-Wallis-Test; α=0.05, * vs control. Results: In both Complex I and II, mitochondrial function was significantly impaired by H 2 O 2 , with ATP synthesis affected more at Complex I and oxygen consumption affected more at Complex II. Addition of P188 did not provide any significant improvement in mitochondrial function. Conclusions: Although P188 significantly reduced IR injury when given during reperfusion in a pig model of MI, it does not appear to provide direct protection to mitochondria in this in-vitro model. Whether the exposure to H 2 O 2 causes the appropriate injury for P188 to become effective remains to be elucidated.

Abstract P352: Prostaglandin E2 Reduces Mitochondrial Function in Adult Mouse Cardiomyocytes

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Pamela Harding ◽  
Timothy D Bryson ◽  
Indrani Datta ◽  
Yun Wang ◽  
Albert Levin
Keyword(s):  
Membrane Potential ◽  
Ejection Fraction ◽  
Prostaglandin E2 ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Function ◽  
Complex I ◽  
Mitochondrial Membrane ◽  
Receptor Subtypes ◽  
Atp Levels ◽  
Complex I Activity

Hypertension is a leading cause of heart failure and both conditions are characterized by increased prostaglandin E2 (PGE2) which signals through 4 receptor subtypes (EP1-EP4) to elicit diverse physiologic effects. We previously reported that cardiomyocyte-specific deletion of the EP4 receptor results in a phenotype of dilated cardiomyopathy in male mice that is characterized by reduced ejection fraction. Subsequent gene array on left ventricles from these mice, coupled with Ingenuity Pathway Analysis (IPA) demonstrated that genes differentiating WT mice and EP4 KO mice with low ejection fraction were significantly overrepresented in mitochondrial (p=2.51x10 -28 ) and oxidative phosphorylation (p=3.16 x10 -30 ) pathways. We therefore hypothesized that PGE2 could reduce mitochondrial function. To test this hypothesis, we used isolated mouse cardiomyocytes (AVM) from 16-18 week old male C57Bl/6 mice and treated them with 1 μM PGE2 for various times. Mitochondrial gene expression was examined using a RT-profiler kit for mitochondrial energy metabolism, complex I activity with a spectrophotometric assay, ATP levels with a bioluminescence assay and mitochondrial membrane potential using JC-1 staining. Treatment of AVM with PGE2 for 4 hrs reduced expression of multiple genes from mitochondrial pathways including sub units of mitochondrial NADH dehydrogenase ubiquinone flavoprotein (Nduf), a component of complex I. In accord with the mRNA data, Complex I activity was reduced by 50% (p < 0.05) by 4 hr treatment with PGE2, from 1.32 ± 0.36 to 0.66 ± 0.08 mOD/min. Cytochrome c oxidase subunit 8 (Cox8c) mRNA was also reduced from a control value of 1.00 to -1.75 ± 0.20 (p < 0.005) after PGE2 treatment. Immuno-fluorescence showed that JC-1 aggregates were reduced after 1 or 3 hr treatment with either 1 μM PGE2 or the EP3 agonist, sulprostone, suggesting reduced mitochondrial membrane potential. Subsequent experiments also showed that ATP levels were reduced 16% from 11.18 ± 0.71 nmol to 9.39 ± 0.83 nmol after treatment with sulprostone for only 1 hr. Taken together, these results suggest that increased PGE2 in hypertension may contribute to impaired mitochondrial function and provide yet another link between inflammation and cardiac dysfunction.

scholarly journals Dopamine modulates mitochondrial function in viable SH-SY5Y cells possibly via its interaction with complex I: Relevance to dopamine pathology in schizophrenia

2008 ◽  
Vol 1777 (2) ◽  
pp. 173-185 ◽  
Author(s):  
Hanit Brenner-Lavie ◽  
Ehud Klein ◽  
Rosa Zuk ◽  
Haifa Gazawi ◽  
Predrage Ljubuncic ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Complex I

Fenofibrate Impairs Rat Mitochondrial Function by Inhibition of Respiratory Complex I

2004 ◽  
Vol 311 (1) ◽  
pp. 109-114 ◽  
Author(s):  
Barbara Brunmair ◽  
Andrea Lest ◽  
Katrin Staniek ◽  
Florian Gras ◽  
Nicole Scharf ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Complex I ◽  
Respiratory Complex ◽  
Respiratory Complex I

Mitochondrial Dysfunction in Sepsis: Evidence from Bacteraemic Baboons and Endotoxaemic Rabbits

2002 ◽  
Vol 22 (1) ◽  
pp. 99-113 ◽  
Author(s):  
Frank Norbert Gellerich ◽  
Sonata Trumbeckaite ◽  
Jens Rüdiger Opalka ◽  
Johannes Frank Gellerich ◽  
Ying Chen ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Respiratory Chain ◽  
Mitochondrial Function ◽  
Complex I ◽  
Current Knowledge ◽  
Mitochondrial Respiratory Chain ◽  
Perfused Heart ◽  
E Coli ◽  
Mitochondrial Functions ◽  
Dose Dependent Decrease

Mitochondria, that provide most of the ATP needed for cell work, and that play numerous specific functions in biosyntheses and degradations, as well as contributing to Ca2+; signaling, also play a key role in the pathway to cell death. Impairment of mitochondrial functions caused by mutations of mt-genome, and by acute processes, are responsible for numerous diseases. The involvement of impaired mitochondria in the pathogenesis of sepsis is discussed. By means of the skinned fiber technique and high resolution respirometry, we have detected significantly reduced rates of mitochondrial respiration in heart and skeletal muscle of endotoxaemic rabbits. Mitochondria from heart were more affected than those from skeletal muscle. Decreased respiration rates were accompanied by reduced activities of complex I+III of the respiratory chain. Endotoxin-caused impairment was also detectable at the level of the Langendorff perfused heart, where the coronary vascular resistance was significantly increased. For an investigation of the influence of bacteraemia on the mitochondrial respiratory chain, baboons were made septic by infusion of high and low amounts of E. coli. For complex I+III and II+III, a clear dose-dependent decrease was detectable and in animals which died in septic shock, a further decrease of enzyme activities in comparison to the controls were found. These results are discussed in the light of current knowledge on the role of mitochondria in cell pathology in respect to sepsis. In conclusion, we present evidence that mitochondrial function is disturbed during sepsis. Besides ischaemic and poison-induced disturbances of mitochondrial function, sepsis is a further example of an acute disease where impaired mitochondria have to be taken into account.

scholarly journals Intellectual disability-associated factor Zbtb11 cooperates with NRF-2/GABP to control mitochondrial function

2019 ◽  
Author(s):  
Brooke C. Wilson ◽  
Lena Boehme ◽  
Ambra Annibali ◽  
Alan Hodgkinson ◽  
Thomas S. Carroll ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Mitochondrial Function ◽  
Complex I ◽  
Target Genes ◽  
Cellular Functions ◽  
Experimental Modelling ◽  
Nuclear Respiratory Factor ◽  
Nuclear Respiratory Factor 2 ◽  
Respiratory Complex I ◽  
Complex I Assembly

AbstractZbtb11 is a conserved transcription factor mutated in families with hereditary intellectual disability. Its precise molecular and cellular functions are currently unknown, precluding our understanding of the aetiology of this disease. Using a combination of functional genomics, genetic and biochemical approaches here we show that Zbtb11 plays essential roles in maintaining the homeostasis of mitochondrial function. Mechanistically, we find Zbtb11 facilitates the recruitment of Nuclear Respiratory Factor 2 (NRF-2) to its target promoters, activating a subset of nuclear genes with roles in the biogenesis of respiratory complex I and the mitoribosome. Genetic inactivation of Zbtb11 resulted in a severe complex I assembly defect, impaired mitochondrial respiration, mitochondrial depolarisation, and ultimately proliferation arrest and cell death. Experimental modelling of the pathogenic human mutations showed these have a destabilising effect on the protein, resulting in reduced Zbtb11 dosage, down-regulation of its target genes, and impaired complex I biogenesis. Our study establishes Zbtb11 as a novel essential mitochondrial regulator, improves our understanding of the transcriptional mechanisms of nuclear control over mitochondria, and provides a rationale for the aetiology of Zbtb11-associated intellectual disability.

scholarly journals An Isolated Complex V Inefficiency and Dysregulated Mitochondrial Function in Immortalized Lymphocytes from ME/CFS Patients

2020 ◽  
Author(s):  
Daniel Missailidis ◽  
Sarah Annesley ◽  
Claire Allan ◽  
Oana Sanislav ◽  
Brett Lidbury ◽  
...  
Keyword(s):  
Steady State ◽  
Fatty Acid ◽  
Mitochondrial Function ◽  
Complex I ◽  
Atp Synthesis ◽  
Beta Oxidation ◽  
Respiratory Capacity ◽  
Respiratory Complexes ◽  
Stress Sensing ◽  
Mitochondrial Respiratory

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is an enigmatic condition characterized by exacerbation of symptoms after exertion (post-exertional malaise or &ldquo;PEM&rdquo;), and by fatigue whose severity and associated requirement for rest are excessive and disproportionate to the fatigue-inducing activity. There is no definitive molecular marker or known underlying pathological mechanism for the condition. Increasing evidence for aberrant energy metabolism suggests a role for mitochondrial dysfunction in ME/CFS. Our objective was therefore to measure mitochondrial function and cellular stress sensing in actively metabolising patient blood cells. We immortalized lymphoblasts isolated from 51 ME/CFS patients diagnosed according to the Canadian Consensus Criteria and an age- and gender-matched control group. Parameters of mitochondrial function and energy stress sensing were assessed by Seahorse extracellular flux analysis, proteomics, and an array of additional biochemical assays. As a proportion of the basal oxygen consumption rate (OCR), the rate of ATP synthesis by Complex V was significantly reduced in ME/CFS lymphoblasts, while significant elevations were observed in Complex I OCR, maximum OCR, spare respiratory capacity, nonmitochondrial OCR and &ldquo;proton leak&rdquo; as a proportion of the basal OCR. This was accompanied by a reduction of mitochondrial membrane potential, chronically hyperactivated TOR Complex I stress signalling and upregulated expression of mitochondrial respiratory complexes, fatty acid transporters and enzymes of the &beta;-oxidation and TCA cycles. By contrast, mitochondrial mass and genome copy number, as well as glycolytic rates and steady state ATP levels were unchanged. Our results suggest a model in which ME/CFS lymphoblasts have a Complex V defect accompanied by compensatory upregulation of their respiratory capacity that includes the mitochondrial respiratory complexes, membrane transporters and enzymes involved in fatty acid &beta;-oxidation. This homeostatically returns ATP synthesis and steady state levels to &ldquo;normal&rdquo; in the resting cells, but may leave them unable to adequately respond to acute increases in energy demand as the relevant homeostatic pathways are already activated.

scholarly journals INTOXICAÇÃO SUBAGUDA AO MANGANÊS EM RATOS WISTAR ADULTOS: AVALIAÇÃO DE PARÂMETROS OXIDATIVOS NO SNC E DEPOSIÇÃO DO METAL EM DIFERENTES TECIDOS

2018 ◽  
Vol 7 (2) ◽  
pp. 193-210
Author(s):  
Maria Victória Branco Flores ◽  
Tuany Eichwald ◽  
Analú Mantovani ◽  
Viviane Glaser ◽  
Carine Raquel Richter Schimitz ◽  
...  
Keyword(s):  
Body Weight ◽  
Mitochondrial Function ◽  
Complex I ◽  
Body Weight Gain ◽  
Thiobarbituric Acid ◽  
Significant Inhibition ◽  
The Body ◽  
Control Group ◽  
Peripheral Tissues ◽  
The Brain

O Manganês (Mn) é um metal essencial para o organismo. É distribuído no ambiente e utilizado em processos industriais. Apesar de essencial, é neurotóxico à exposições cumulativas, causando uma desordem neurológica, o Manganismo. O estudo avaliou o efeito da administração subaguda de Mn sob a forma de cloreto e acetato de Mn, sobre a função mitocondrial e parâmetros oxidativos no encéfalo, bem como o acúmulo deste metal no encéfalo e tecidos periféricos de ratos adultos. Os ratos receberam 6 mg/kg de Mn i.p. na forma de cloreto ou acetato de Mn, 5 dias/semana por 4 semanas. O grupo controle recebeu solução salina 0,9% pela mesma via de administração e mesmo período. Foi mensurada a concentração de substâncias reativas ao ácido tiobarbitúrico (TBARS) e grupamentos NPSH, a atividade dos complexos I e II da cadeia respiratória no encéfalo e/ou estruturas cerebrais, bem como o peso corporal e a concentração de Mn e Fe no soro, encéfalo, tecido renal e hepático. Foi observada uma diminuição no ganho de peso corporal dos animais que receberam o Mn, um aumento na concentração/depósito de Mn no soro, encéfalo e tecido renal, tanto na forma de cloreto e acetato de Mn, quando comparados com o grupo controle. Além disso, houve um aumento significativo no conteúdo de NPSH no encéfalo e, embora não significativo, uma tendência de aumento da concentração de TBARS, no grupo que recebeu cloreto de Mn. Ainda, foi verificada uma inibição na atividade do complexo I no estriado dos animais expostos ao cloreto de Mn. Não houve diferença entre os grupos nas atividades do complexo I e II no encéfalo e hipocampo. Em conjunto, os dados indicam que a exposição ao Mn em baixas doses contribui para o desenvolvimento de estresse oxidativo e disfunção mitocondrial no SNC, com aparente predileção de dano ao estriado.Palavras-chave: Manganês. Exposição subaguda. Parâmetros oxidativos. Função mitocondrial. MANGANESE SUBACUTE INTOXICATION IN ADULT WISTAR RATS: EVALUATION OF OXIDATIVE PARAMETERS IN CNS AND METAL DEPOSITION IN DIFFERENT TISSUES ABSTRACT: Mn is an essential metal to the organism. It is distributed in the environment and used in industrial processes. Although essential, it is neurotoxic to cumulative exposures, and can cause a neurological disorder, called Manganism. This study evaluated the effect of subacute Mn as chloride and acetate of Mn administration on mitochondrial function and oxidative parameters in adult rat brain, as well as the accumulation of this metal in the brain and peripheral tissues. The rats received 6 mg/kg of Mn i.p., as Mn chloride or Mn acetate, 5 days/week for 4 weeks. The control group received 0.9% of saline solution in the same way of administration and in the same period. It was measured the concentration of thiobarbituric acid reactive substances (TBARS) and NPSH groups, the activity of mitochondrial complex I and II in brain and/or in the brain structures, as well as the body weight and the concentration of Mn and Fe accumulation. It was observed a decrease on body weight gain in animals exposed to Mn and an increase of concentration/deposit of Mn in serum, brain and kidney, in the both Mn chloride and acetate form when compared to the control group. In addition, there was a significant increase in brain NPSH content and, although it was not significant, a trend of increasing on TBARS concentration in the group that received Mn. Besides that, a significant inhibition of complex I activity was observed in the striatum of the animals exposed to Mn. There was not difference between groups on complex I and II in the brain and hippocampus. Together, these data indicate that exposure to Mn at low doses contributes to the development of oxidative stress and mitochondrial dysfunction in the CNS, with apparent predilection of striatum damage.Keywords: Manganese. Subacute exposure. Oxidative parameters. Mitochondrial function.

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