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Skalska 2009 Int J Mol Sci + (Abstract: The mitochondrial response to ch … Abstract: The mitochondrial response to changes of cytosolic calcium concentration has a strong impact on neuronal cell metabolism and viability. We observed that Ca2+ additions to isolated rat brain mitochondria induced in potassium ion containing media a mitochondrial membrane potential depolarization and an accompanying increase of mitochondrial respiration. These Ca2+ effects can be blocked by iberiotoxin and charybdotoxin, well known inhibitors of large conductance potassium channel (BKCa channel). Furthermore, NS1619 – a BKCa channel opener – induced potassium ion–specific effects on brain mitochondria similar to those induced by Ca2+. These findings suggest the presence of a calcium-activated, large conductance potassium channel (sensitive to charybdotoxin and NS1619), which was confirmed by reconstitution of the mitochondrial inner membrane into planar lipid bilayers. The conductance of the reconstituted channel was 265 pS under gradient (50/450 mM KCl) conditions. Its reversal potential was equal to 50 mV, which proved that the examined channel was cation-selective. We also observed immunoreactivity of anti-β4 subunit (of the BKCa channel) antibodies with ~26 kDa proteins of rat brain mitochondria. Immunohistochemical analysis confirmed the predominant occurrence of anti-β4 subunit in neuronal mitochondria. We hypothesize that the mitochondrial BKCa channel represents a calcium sensor, which can contribute to neuronal signal transduction and survival.hannel represents a calcium sensor, which can contribute to neuronal signal transduction and survival.)
Klein 2018 Int J Digit Libr + (Academic publishers claim that they add va … Academic publishers claim that they add value to scholarly communications by coordinating reviews and contributing and enhancing text during publication. These contributions come at a considerable cost: US academic libraries paid $1.7 billion for serial subscriptions in 2008 alone. Library budgets, in contrast, are flat and not able to keep pace with serial price inflation. We have investigated the publishers’ value proposition by conducting a comparative study of pre-print papers from two distinct science, technology, and medicine corpora and their final published counterparts. This comparison had two working assumptions: (1) If the publishers’ argument is valid, the text of a pre-print paper should vary measurably from its corresponding final published version, and (2) by applying standard similarity measures, we should be able to detect and quantify such differences. Our analysis revealed that the text contents of the scientific papers generally changed very little from their pre-print to final published versions. These findings contribute empirical indicators to discussions of the added value of commercial publishers and therefore should influence libraries’ economic decisions regarding access to scholarly publications.egarding access to scholarly publications.)
Teixeira 2022 J Gen Philos Sci + (Academic publishing is undergoing a highly … Academic publishing is undergoing a highly transformative process, and many established rules and value systems that are in place, such as traditional peer review (TPR) and preprints, are facing unprecedented challenges, including as a result of post-publication peer review. The integrity and validity of the academic literature continue to rely naively on blind trust, while TPR and preprints continue to fail to effectively screen out errors, fraud, and misconduct. Imperfect TPR invariably results in imperfect papers that have passed through varying levels of rigor of screening and validation. If errors or misconduct were not detected during TPR's editorial screening, but are detected at the post-publication stage, an opportunity is created to correct the academic record. Currently, the most common forms of correcting the academic literature are errata, corrigenda, expressions of concern, and retractions or withdrawals. Some additional measures to correct the literature have emerged, including manuscript versioning, amendments, partial retractions and retract and replace. Preprints can also be corrected if their version is updated. This paper discusses the risks, benefits and limitations of these forms of correcting the academic literature.rms of correcting the academic literature.)
Coelho 2016 Oncol Rep + (Acceleration of glycolysis is a characteri … Acceleration of glycolysis is a characteristic of neoplasia. Previous studies have shown that a metabolic shift occurs in many tumors and correlates with a negative prognosis. The present study aimed to investigate the glycolytic profile of thyroid carcinoma cell lines. We investigated glycolytic and oxidative parameters of two thyroid carcinoma papillary cell lines (BCPAP and TPC1) and the non-tumor cell line NTHY-ori. All carcinoma cell lines showed higher rates of glycolysis efficiency, when compared to NTHY-ori, as assessed by a higher rate of glucose consumption and lactate production. The BCPAP cell line presented higher rates of growth, as well as elevated intracellular ATP levels, compared to the TPC1 and NTHY-ori cells. We found that glycolysis and activities of pentose phosphate pathway (PPP) regulatory enzymes were significantly different among the carcinoma cell lines, particularly in the mitochondrial hexokinase (HK) activity which was higher in the BCPAP cells than that in the TPC1 cell line which showed a balanced distribution of HK activity between cytoplasmic and mitochondrial subcellular localizations. However, TPC1 had higher levels of glucose‑6-phosphate dehydrogenase activity, suggesting that the PPP is elevated in this cell type. Using high resolution respirometry, we observed that the Warburg effect was present in the BCPAP and TPC1 cells, characterized by low oxygen consumption and high reactive oxygen species production. Overall, these results indicate that both thyroid papillary carcinoma cell lines showed a glycolytic profile. Of note, BCPAP cells presented some relevant differences in cell metabolism compared to TPC1 cells, mainly related to higher mitochondrial-associated HK activity.gher mitochondrial-associated HK activity.)
Acclimatization and High Altitude Illness - Facts and Myths 2017 Brixen Dolomites IT + (Acclimatization and High Altitude Illness - Facts and Myths, Brixen Dolomites, IT)
Arias-Reyes 2023 MitoFit + (Acclimatization to high altitude relies on … Acclimatization to high altitude relies on adjustments of cellular metabolism that optimize oxygen use and energy production. In tissues with high energy demand and almost exclusive reliance on aerobic metabolism such as the brain, hypoxia is a particularly strong stressor, however, strategies to adjust metabolic pathways for successful high-altitude acclimatization remain poorly understood. Compared to SD rats, FVB mice show successful acclimatization to high altitude, we, therefore, used this model to investigate metabolic adjustments in the retrosplenial cortex (a key area of the brain involved in spatial learning and navigation) in normoxia and during acclimatization to hypoxia (12 % O2 – 1, 7, and 21 days). We measured in simultaneous the rates of ATP synthesis and O2 consumption in fresh permeabilized brain samples by coupled high-resolution respirometry and fluorometry. We quantified the citrate synthase (CS) activity as an index of mitochondrial content, the transcriptional regulation of genes involved in mitochondrial dynamics; and the activity of enzymes representative of the glycolytic, aerobic, and anaerobic metabolism. Our findings show that acclimatization to hypoxia significantly increases ATP synthesis in mice and to a lower extent in rats. In mice, this occurs in parallel with a reduction of O2 consumption, and a three-fold increase in the P»/O ratio. In rats, a six-fold increase in CS activity and altered mitochondrial dynamics gene expression are evident. Finally, activities of glycolytic, aerobic, or anaerobic enzymes remain overall unchanged in both species except for a transient glycolytic and anaerobic peak at day 7 in mice. Altogether, our results show that chronic hypoxia optimizes the efficiency of mitochondrial ATP synthesis in the retrosplenial cortex of mice. Contrastingly, rats sustain the production of ATP only by increasing mitochondrial content and altering mitochondrial dynamics, suggesting drastic mitochondrial malfunctions. ing mitochondrial dynamics, suggesting drastic mitochondrial malfunctions. )
Schoenfeld 2016 J Cereb Blood Flow Metab + (According to recent reports, systemic trea … According to recent reports, systemic treatment of rats with methylpalmoxirate (carnitine palmitoyltransferase-1 inhibitor) decreased peroxidation of polyunsaturated fatty acids in brain tissue. This was taken as evidence of mitochondrial β-oxidation in brain, thereby contradicting long-standing paradigms of cerebral metabolism, which claim that β-oxidation of activated fatty acids has minor importance for brain energy homeostasis. We addressed this controversy. Our experiments are the first direct experimental analysis of this question. We fueled isolated brain mitochondria or rat brain astrocytes with octanoic acid, but octanoic acid does not enhance formation of reactive oxygen species, neither in isolated brain mitochondria nor in astrocytes, even at limited hydrogen delivery to mitochondria. Thus, octanoic acid or l-octanoylcarnitine does not stimulate H2O2 release from brain mitochondria fueled with malate, in contrast to liver mitochondria (2.25-fold rise). This does obviously not support the possible occurrence of β-oxidation of the fatty acid octanoate in the brain. We conclude that a proposed inhibition of β-oxidation does not seem to be a helpful strategy for therapies aiming at lowering oxidative stress in cerebral tissue. This question is important, since oxidative stress is the cause of neurodegeneration in numerous neurodegenerative or inflammatory disease situations.© The Author(s) 2016.erative or inflammatory disease situations. © The Author(s) 2016.)
Roskams T Falk Workshop Inflammation & Cancer + (According to the cancer stem cell concept, … According to the cancer stem cell concept, hepatocellular carcinoma (HCC) consists of a hierarchy of cell populations, of which the very small cancer stem cell population is the one that has the growth and metastatic potential of the tumour. The other neoplastic cells are offspring of the cancer stem cells and each can differentiate a little differently, according to the local microenvironment in each part of the tumor, hence explaining the enormous phenotypic heterogeneity of a neoplasm. Current therapeutic strategies mostly target rapidly growing differentiated tumour cells. However the results are often unsatisfactory because of the chemoresistance of HCC. New therapies targeting cancer stem cells should therefore be developed. A prerequisite is a good understanding of the mechanisms of activation and differentiation of normal stem/progenitor cells in normal and diseased liver. Hepatocytes and cholangiocytes have stem cell features, but also progenitor cells, located in the smallest branches of the biliary tree. These cells are especially activated in the cirrhotic stage of chronic liver diseases, the stage in which HCC develops. HCC with progenitor cell features, possibly reflecting a progenitor cell origin, have a very bad prognosis and therefore should be recognized and treated accordingly.uld be recognized and treated accordingly.)
Huetter 2007 Aging Cell + (According to the free radical theory of ag … According to the free radical theory of aging, reactive oxygen species (ROS) act as a driving force of the aging process, and it is generally believed that mitochondrial dysfunction is a major source of increased oxidative stress in tissues with high content of mitochondria, such as muscle or brain. However, recent experiments in mouse models of premature aging have questioned the role of mitochondrial ROS production in premature aging. To address the role of mitochondrial impairment and ROS production for aging in human muscles, we have analyzed mitochondrial properties in muscle fibres isolated from the vastus lateralis of young and elderly donors. Mitochondrial respiratory functions were addressed by high-resolution respirometry, and ROS production was analyzed by in situ staining with the redox-sensitive dye dihydroethidium. We found that aged human skeletal muscles contain fully functional mitochondria and that the level of ROS production is higher in young compared to aged muscle. Accordingly, we could not find any increase in oxidative modification of proteins in muscle from elderly donors. However, the accumulation of lipofuscin was identified as a robust marker of human muscle aging. The data support a model, where ROS-induced molecular damage is continuously removed, preventing the accumulation of dysfunctional mitochondria despite ongoing ROS production.tochondria despite ongoing ROS production.)
Huisamen 2015 Abstract MiPschool Cape Town 2015 + (According to the latest statistics, variou … According to the latest statistics, various cardiovascular diseasesaccounted for 8.3% of natural deaths in South Africa during 2013,ranking the 6th place as cause of mortality. With the efficiencyof therapies aimed at decreasing mortality from heart disease, lifeexpectancy increased. As result of this, the focus of recent researchchanged towards understanding the energy demands of the heart inorder to optimize function. Because of its high energetic needs, thehuman heart utilizes between 3.5 and 6 kg of ATP per day to function.This is produced by its mitochondrial populations which occupy up to50% of the volume of a cardiomyocyte. A close link therefore existsbetween mitochondrial dysfunction and heart disease. In addition, thereis growing recognition that inborn errors of metabolism can influencecardiomyocyte dysfunction [1] and that primary inherited mitochondrialdiseases display a full spectrum of cardiac disorders [2].ATM is a 350kDa serine/threonine protein kinase displaying homologiesto the large protein family of PI3-Kinases, although it lacks the ability tophosphorylate lipids [3]. It came under scrutiny because of the disease,Ataxia-telangiectasie (A-T), which is an autosomal, recessive disorderthat progressively affects multiple organs. This disease is caused bymutations in the Atm gene, resulting in lack or inactivation of the ATMprotein [4]. ATM in the cell can be localized to the nucleus, cytoplasm ofmitochondria.We became interested in myocardial ATM because it was found thatskeletal muscle of insulin resistant, obese rats had dramatically reducedlevels of the so-called ATM protein, in association with the well-knownreduced activation of the insulin/ phosphatidylinositol 3 kinases (PI3-kinase)/PKB/Akt pathway, which is the main mechanism of relaying themetabolic effects of insulin [5]. Foster et al [6] found structural and functional changes in the hearts of ATM KO mice, using echocardiography andDoppler echocardiography.The mitochondrial association of ATM protein kinase plays an importantrole in its integrity and functioning such that ATM deficiency results indefects in mitochondrial respiration [7]. ATM also regulates mitochondrialbiogenesis and DNA content [8]. In addition, it was demonstrated that amitochondria-targeted antioxidant MitoQ, could decrease the features ofthe metabolic syndrome in ATM+/-ApoE-/- mice [9]. This may be becauseone of the mechanisms known to activate the ATM protein is increasedoxidative stress. Activated ATM initiates an anti-oxidant response basedon a metabolic shift while, in fibroblast cell lines, inactivation of ATMis associated with increased ROS levels followed by expression andactivation of the transcription factor HIF-1alpha [10]. the transcription factor HIF-1alpha [10].)
Kozieł 2011 J Invest Dermatol + (According to the mitochondrial theory of a … According to the mitochondrial theory of aging, reactive oxygen species (ROS) derived primarily from mitochondria cause cumulative oxidative damage to various cellular molecules and thereby contribute to the aging process. On the other hand, a pivotal role of the proteasome, as a main proteolytic system implicated in the degradation of oxidized proteins during aging, is suggested. In this study, we analyzed mitochondrial function in dermal fibroblasts derived from biopsies obtained from healthy young, middle-aged, and old donors. We also determined proteasome activity in these cells, using a degron-destabilized green fluorescent protein (GFP)-based reporter protein. We found a significant decrease in mitochondrial membrane potential in samples from aged donors, accompanied by a significant increase in ROS levels. Respiratory activity was not significantly altered with donor age, probably reflecting genetic variation. Proteasome activity was significantly decreased in fibroblasts from middle-aged donors compared with young donors; fibroblasts derived from the oldest donors displayed a high heterogeneity in this assay. We also found intraindividual coregulation of mitochondrial and proteasomal activities in all human fibroblast strains tested, suggesting that both systems are interdependent. Accordingly, pharmacological inhibition of the proteasome led to decreased mitochondrial function, whereas inhibition of mitochondrial function in turn reduced proteasome activity.ction in turn reduced proteasome activity.)
Schiffer 2013 Abstract MiP2013 + (According to the rate-of-living and oxidat … According to the rate-of-living and oxidative damage theory of aging, extended lifespan is predicted by low energy metabolism and low reactive oxygen species production rates. Recently, several studies show that dietary inorganic nitrate mainly present in vegetables can reduce oxygen consumption during physical exercise in humans [1] and contribute to attenuated oxidative stress in animal models of disease [2]. Nitrate accumulates in saliva and is bioactivated through reduction to nitrite by oral bacteria. We examined the effects of dietary nitrate on basal metabolic rate (BMR) and markers of oxidative stress in man using a double-blind, randomized cross over design. 15 young healthy males volunteered and indirect calorimetry was used to determine basal metabolic rate after three days of dietary intervention with sodium nitrate (NaNO3, 0.1 mmol∙kg-1∙day-1) or placebo (NaCl). The administered amount of nitrate resembles what is found in 100-300 g of nitrate rich vegetables such as beetroot or spinach. The intervention reduced BMR by 4.3% after nitrate administration compared with placebo (p<0.02). A strong negative correlation was found between the change in salivary nitrate and the change in BMR (r2=0.72; p<0.002). In addition, nitrate supplementation reduced plasma levels of malondialdehyde, indicating lower oxidative stress as a result of the intervention. Thyroid hormone status was unaffected.The cuisines of cultures known for their longevity are usually rich in vegetables and future studies will reveal whether this life span extension is linked to the high nitrate content in this food group. to the high nitrate content in this food group.)
Nelson 2016 J Fish Biol + (Accounting for energy use by fishes has be … Accounting for energy use by fishes has been taking place for over 200 years. The original, and continuing gold standard for measuring energy use in terrestrial animals, is to account for the waste heat produced by all reactions of metabolism, a process referred to as direct calorimetry. Direct calorimetry is not easy or convenient in terrestrial animals and is extremely difficult in aquatic animals. Thus, the original and most subsequent measurements of metabolic activity in fishes have been measured via indirect calorimetry. Indirect calorimetry takes advantage of the fact that oxygen is consumed and carbon dioxide is produced during the catabolic conversion of foodstuffs or energy reserves to useful ATP energy. As measuring [CO2] in water is more challenging than measuring [O2], most indirect calorimetric studies on fishes have used the rate of O2 consumption. To relate measurements of O2 consumption back to actual energy usage requires knowledge of the substrate being oxidized. Many contemporary studies of O2 consumption by fishes do not attempt to relate this measurement back to actual energy usage. Thus, the rate of oxygen consumption has become a measurement in its own right that is not necessarily synonymous with metabolic rate. Because all extant fishes are obligate aerobes (many fishes engage in substantial net anaerobiosis, but all require oxygen to complete their life cycle), this discrepancy does not appear to be of great concern to the fish biology community, and reports of fish oxygen consumption, without being related to energy, have proliferated. Unfortunately, under some circumstances, these measures can be quite different from one another. A review of the methodological history of the two measurements and a look towards the future are included.view of the methodological history of the two measurements and a look towards the future are included.)
Fitzgerald 2024 J Cachexia Sarcopenia Muscle + (Accumulating evidence has demonstrated tha … Accumulating evidence has demonstrated that chronic tobacco smoking directly contributes to skeletal muscle dysfunction independent of its pathological impact to the cardiorespiratory systems. The mechanisms underlying tobacco smoke toxicity in skeletal muscle are not fully resolved. In this study, the role of the aryl hydrocarbon receptor (AHR), a transcription factor known to be activated with tobacco smoke, was investigated.AHR related gene (mRNA) expression was quantified in skeletal muscle from adult controls and patients with chronic obstructive pulmonary disease (COPD), as well as mice with and without cigarette smoke exposure. Utilizing both skeletal muscle-specific AHR knockout mice exposed to chronic repeated (5 days per week for 16 weeks) cigarette smoke and skeletal muscle-specific expression of a constitutively active mutant AHR in healthy mice, a battery of assessments interrogating muscle size, contractile function, mitochondrial energetics, and RNA sequencing were employed.Skeletal muscle from COPD patients (N = 79, age = 67.0 ± 8.4 years) had higher levels of AHR (P = 0.0451) and CYP1B1 (P < 0.0001) compared to healthy adult controls (N = 16, age = 66.5 ± 6.5 years). Mice exposed to cigarette smoke displayed higher expression of Ahr (P = 0.008), Cyp1b1 (P < 0.0001), and Cyp1a1 (P < 0.0001) in skeletal muscle compared to air controls. Cigarette smoke exposure was found to impair skeletal muscle mitochondrial oxidative phosphorylation by ~50% in littermate controls (Treatment effect, P < 0.001), which was attenuated by deletion of the AHR in muscle in male (P = 0.001), but not female, mice (P = 0.37), indicating there are sex-dependent pathological effects of smoking-induced AHR activation in skeletal muscle. Viral mediated expression of a constitutively active mutant AHR in the muscle of healthy mice recapitulated the effects of cigarette smoking by decreasing muscle mitochondrial oxidative phosphorylation by ~40% (P = 0.003).These findings provide evidence linking chronic AHR activation secondary to cigarette smoke exposure to skeletal muscle bioenergetic deficits in male, but not female, mice. AHR activation is a likely contributor to the decline in muscle oxidative capacity observed in smokers and AHR antagonism may provide a therapeutic avenue aimed to improve muscle function in COPD.eutic avenue aimed to improve muscle function in COPD.)
Ying 2008 Antioxid Redox Signal + (Accumulating evidence has suggested that N … Accumulating evidence has suggested that NAD (including NAD+ and NADH) and NADP (including NADP+ and NADPH) could belong to the fundamental common mediators of various biological processes, including energy metabolism, mitochondrial functions, calcium homeostasis, antioxidation/generation of oxidative stress, gene expression, immunological functions, aging, and cell death: First, it is established that NAD mediates energy metabolism and mitochondrial functions; second, NADPH is a key component in cellular antioxidation systems; and NADH-dependent reactive oxygen species (ROS) generation from mitochondria and NADPH oxidase-dependent ROS generation are two critical mechanisms of ROS generation; third, cyclic ADP-ribose and several other molecules that are generated from NAD and NADP could mediate calcium homeostasis; fourth, NAD and NADP modulate multiple key factors in cell death, such as mitochondrial permeability transition, energy state, poly(ADP-ribose) polymerase-1, and apoptosis-inducing factor; and fifth, NAD and NADP profoundly affect aging-influencing factors such as oxidative stress and mitochondrial activities, and NAD-dependent sirtuins also mediate the aging process. Moreover, many recent studies have suggested novel paradigms of NAD and NADP metabolism. Future investigation into the metabolism and biological functions of NAD and NADP may expose fundamental properties of life, and suggest new strategies for treating diseases and slowing the aging process.ew strategies for treating diseases and slowing the aging process.)
Abu Bakar 2020 Eur J Pharmacol + (Accumulating evidence indicates that adipo … Accumulating evidence indicates that adipose tissue inflammation and mitochondrial dysfunction in skeletal muscle are inextricably linked to obesity and insulin resistance. Celastrol, a bioactive compound derived from the root of Tripterygium wilfordii exhibits a number of attributive properties to attenuate metabolic dysfunction in various cellular and animal disease models. However, the underlying therapeutic mechanisms of celastrol in the obesogenic environment "in vivo" remain elusive. Therefore, the current study investigated the metabolic effects of celastrol on insulin sensitivity, inflammatory response in adipose tissue and mitochondrial functions in skeletal muscle of the high fat diet (HFD)-induced obese rats. Our study revealed that celastrol supplementation at 3 mg/kg/day for 8 weeks significantly reduced the final body weight and enhanced insulin sensitivity of the HFD-fed rats. Celastrol noticeably improved insulin-stimulated glucose uptake activity and increased expression of plasma membrane GLUT4 protein in skeletal muscle. Moreover, celastrol-treated HFD-fed rats showed attenuated inflammatory responses via decreased NF-κB activity and diminished mRNA expression responsible for classically activated macrophage (M1) polarization in adipose tissues. Significant improvement of muscle mitochondrial functions and enhanced antioxidant defense machinery via restoration of mitochondrial complexes I + III linked activity were effectively exhibited by celastrol treatment. Mechanistically, celastrol stimulated mitochondrial biogenesis attributed by upregulation of the adenosine monophosphate-activated protein kinase (AMPK) and sirtuin 1 (SIRT1) signaling pathways. Together, these results further demonstrate heretofore the conceivable therapeutic mechanisms of celastrol "in vivo" against HFD-induced obesity mediated through attenuation of inflammatory response in adipose tissue and enhanced mitochondrial functions in skeletal muscle.itochondrial functions in skeletal muscle.)
Arena 2018 Mol Cell + (Accumulating evidence indicates that the M … Accumulating evidence indicates that the MDM2 oncoprotein promotes tumorigenesis beyond its canonical negative effects on the p53 tumor suppressor, but these p53-independent functions remain poorly understood. Here, we show that a fraction of endogenous MDM2 is actively imported in mitochondria to control respiration and mitochondrial dynamics independently of p53. Mitochondrial MDM2 represses the transcription of NADH-dehydrogenase 6 (MT-ND6) ''in vitro'' and ''in vivo'', impinging on respiratory complex I activity and enhancing mitochondrial ROS production. Recruitment of MDM2 to mitochondria increases during oxidative stress and hypoxia. Accordingly, mice lacking MDM2 in skeletal muscles exhibit higher MT-ND6 levels, enhanced complex I activity, and increased muscular endurance in mild hypoxic conditions. Furthermore, increased mitochondrial MDM2 levels enhance the migratory and invasive properties of cancer cells. Collectively, these data uncover a previously unsuspected function of the MDM2 oncoprotein in mitochondria that play critical roles in skeletal muscle physiology and may contribute to tumor progression.y and may contribute to tumor progression.)
Yang 2018 Cell Death Dis + (Accumulating evidence revealed that mesenc … Accumulating evidence revealed that mesenchymal stem cells (MSCs) confer cardioprotection against myocardial infarction (MI). However, the poor survival and engraftment rate of the transplanted cells limited their therapeutic efficacy in the heart. The enhanced leptin production associated with hypoxia preconditioning contributed to the improved MSCs survival. Mitochondrial integrity determines the cellular fate. Thus, we aimed to investigate whether leptin can enhance mitochondrial integrity of human MSCs (hMSCs) to protect against various stress. ''In vivo'', transplantation of leptin-overexpressing hMSCs into the infarcted heart resulted in improved cell viability, leading to enhanced angiogenesis and cardiac function. ''In vitro'', pretreatment of hMSCs with recombinant leptin (hMSCs-Leppre) displayed improved cell survival against severe ischemic condition (glucose and serum deprivation under hypoxia), which was associated with increased mitochondrial fusion. Subsequently, Optic atrophy 1 (OPA1), a mitochondrial inner membrane protein that regulates fusion and cristae structure, was significantly elevated in the hMSCs-Leppre group, and the protection of leptin was abrogated by targeting OPA1 with a selective siRNA. Furthermore, OMA1, a mitochondrial protease that cleaves OPA1, decreased in a leptin-dependent manner. Pretreatment of cells with an inhibitor of the proteasome (MG132), prevented leptin-induced OMA1 degradation, implicating the ubiquitination/proteasome system as a part of the protective leptin pathway. In addition, GSK3 inhibitor (SB216763) was also involved in the degradation of OMA1. In conclusion, in the hostile microenvironment caused by MI, (a) leptin can maintain the mitochondrial integrity and prolong the survival of hMSCs; (b) leptin-mediated mitochondrial integrity requires phosphorylation of GSK3 as a prerequisite for ubiquitination-depended degradation of OMA1 and attenuation of long-OPA1 cleavage. Thus, leptin targeting the GSK3/OMA1/OPA1 signaling pathway can optimize hMSCs therapy for cardiovascular diseases such as MI.can optimize hMSCs therapy for cardiovascular diseases such as MI.)
Yan 2015 BMC Cancer + (Accumulating evidence suggests that breast … Accumulating evidence suggests that breast cancer involves tumour-initiating cells (TICs), which play a role in initiation, metastasis, therapeutic resistance and relapse of the disease. Emerging drugs that target TICs are becoming a focus of contemporary research. Mitocans, a group of compounds that induce apoptosis of cancer cells by destabilising their mitochondria, are showing their potential in killing TICs. In this project, we investigated mitochondrially targeted vitamin E succinate (MitoVES), a recently developed mitocan, for its ''in vitro'' and ''in vivo'' efficacy against TICs.The mammosphere model of breast TICs was established by culturing murine NeuTL and human MCF7 cells as spheres. This model was verified by stem cell marker expression, tumour initiation capacity and chemotherapeutic resistance. Cell susceptibility to MitoVES was assessed and the cell death pathway investigated. ''In vivo'' efficacy was studied by grafting NeuTL TICs to form syngeneic tumours.Mammospheres derived from NeuTL and MCF7 breast cancer cells were enriched in the level of stemness, and the sphere cells featured altered mitochondrial function. Sphere cultures were resistant to several established anti-cancer agents while they were susceptible to MitoVES. Killing of mammospheres was suppressed when the mitochondrial complex II, the molecular target of MitoVES, was knocked down. Importantly, MitoVES inhibited progression of syngeneic HER2(high) tumours derived from breast TICs by inducing apoptosis in tumour cells.These results demonstrate that using mammospheres, a plausible model for studying TICs, drugs that target mitochondria efficiently kill breast tumour-initiating cells.ently kill breast tumour-initiating cells.)
Braganza 2019 Mol Aspects Med + (Accumulating studies demonstrate that mito … Accumulating studies demonstrate that mitochondrial genetics and function are central to determining the susceptibility to, and prognosis of numerous diseases across all organ systems. Despite this recognition, mitochondrial function remains poorly characterized in humans primarily due to the invasiveness of obtaining viable tissue for mitochondrial studies. Recent studies have begun to test the hypothesis that circulating blood cells, which can be obtained by minimally invasive methodology, can be utilized as a biomarker of systemic bioenergetic function in human populations. Here we present the available methodologies for assessing blood cell bioenergetics and review studies that have applied these techniques to healthy and disease populations. We focus on the validation of this methodology in healthy subjects, as well as studies testing whether blood cell bioenergetics are altered in disease, correlate with clinical parameters, and compare with other methodology for assessing human mitochondrial function. Finally, we present the challenges and goals for the development of this emerging approach into a tool for translational research and personalized medicine.Copyright © 2019 Elsevier Ltd. All rights reserved. 2019 Elsevier Ltd. All rights reserved.)
Amaral 2016 J Neurochem + (Accumulation of 2-methylcitric acid (2MCA) … Accumulation of 2-methylcitric acid (2MCA) is observed in methylmalonic and propionic acidemias, which are clinically characterized by severe neurological symptoms. The exact pathogenetic mechanisms of brain abnormalities in these diseases are poorly established and very little has been reported on the role of 2MCA. In the present work we found that 2MCA markedly inhibited ADP-stimulated and uncoupled respiration in mitochondria supported by glutamate, with a less significant inhibition in pyruvate plus malate-respiring mitochondria. However, no alterations occurred when α-ketoglutarate or succinate was used as respiratory substrates, suggesting a defect on glutamate oxidative metabolism. It was also observed that 2MCA decreased ATP formation in glutamate plus malate or pyruvate plus malate-supported mitochondria. Furthermore, 2MCA inhibited glutamate dehydrogenase (GDH) activity at concentrations as low as 0.5 mM. Kinetic studies revealed that this inhibitory effect was competitive in relation to glutamate. In contrast, assays of osmotic swelling in non-respiring mitochondria suggested that 2MCA did not significantly impair mitochondrial glutamate transport. Finally, 2MCA provoked a significant decrease of mitochondrial membrane potential and induced swelling in Ca2+ -loaded mitochondria supported by different substrates. These effects were totally prevented by cyclosporine A plus ADP or ruthenium red, indicating induction of mitochondrial permeability transition (PT). Taken together, our data strongly indicate that 2MCA behaves as a potent inhibitor of glutamate oxidation by inhibiting GDH activity and as a PT inducer, disturbing mitochondrial energy homeostasis. We presume that 2MCA-induced mitochondrial deleterious effects may contribute to the pathogenesis of brain damage in patients affected by methylmalonic and propionic acidemias. This article is protected by copyright. All rights reserved.rticle is protected by copyright. All rights reserved.)
Liu 2002 Proc Natl Acad Sci U S A + (Accumulation of oxidative damage to mitoch … Accumulation of oxidative damage to mitochondria, protein, and nucleic acid in the brain may lead to neuronal and cognitive dysfunction. The effects on cognitive function, brain mitochondrial structure, and biomarkers of oxidative damage were studied after feeding old rats two mitochondrial metabolites, acetyl-l-carnitine (ALCAR) [0.5% or 0.2% (wt/vol) in drinking water], and/or R-alpha-lipoic acid (LA) [0.2% or 0.1% (wt/wt) in diet]. Spatial memory was assessed by using the Morris water maze; temporal memory was tested by using the peak procedure (a time-discrimination procedure). Dietary supplementation with ALCAR and/or LA improved memory, the combination being the most effective for two different tests of spatial memory (''P'' < 0.05; ''P'' < 0.01) and for temporal memory (P < 0.05). Immunohistochemical analysis showed that oxidative damage to nucleic acids (8-hydroxyguanosine and 8-hydroxy-2'-deoxyguanosine) increased with age in the hippocampus, a region important for memory. Oxidative damage to nucleic acids occurred predominantly in RNA. Dietary administration of ALCAR and/or LA significantly reduced the extent of oxidized RNA, the combination being the most effective. Electron microscopic studies in the hippocampus showed that ALCAR and/or LA reversed age-associated mitochondrial structural decay. These results suggest that feeding ALCAR and LA to old rats improves performance on memory tasks by lowering oxidative damage and improving mitochondrial function.dative damage and improving mitochondrial function.)
Schoettl 2015 Endocrinology + (Accumulation of visceral fat is associated … Accumulation of visceral fat is associated with metabolic risk whereas excessive amounts of peripheral fat are considered less problematic. At the same time, altered white adipocyte mitochondrial bioenergetics has been implicated in the pathogenesis of insulin resistance and type 2 diabetes.We therefore investigated whether the metabolic risk of visceral versus peripheral fat coincides with a difference in mitochondrial capacity of white adipocytes. We assessed bioenergetic parameters of subcutaneous inguinal and visceral epididymal white adipocytes from male C57BL/6N mice employing a comprehensive respirometry setup of intact and permeabilized adipocytes as well as isolated mitochondria. Inguinal adipocytes clearly featured a higher respiratory capacity attributable to increased mitochondrial respiratory chain content as compared to epididymal adipocytes. The lower capacity of mitochondria from epididymal adipocytes was accompanied by an increased generation of reactive oxygen species per oxygen consumed. Feeding a high-fat diet for one week reduced white adipocyte mitochondrial capacity, with stronger effects in epididymal when compared to inguinal adipocytes. This was accompanied by impaired body glucose homeostasis. Therefore, the limited bioenergetic performance combined with the proportionally higher generation of reactive oxygen species of visceral adipocytes could be seen as a candidate mechanism mediating the elevated metabolic risk associated with this fat depot.bolic risk associated with this fat depot.)
Gnaiger 1990 Thermochim Acta + (Accurate definitions of efficiency are req … Accurate definitions of efficiency are required to resolve controversies on the significance and comparability of measures of efficiency in biological energetics. This review on concepts of efficiency is arranged into 4 parts. First, some fundamental energy relations of equilibrium and nonequilibrium thermodynamics are defined and placed into a coherent context as relevant for efficiency in biology. The classical expression of the Carnot efficiency of a heat engine obtains a new meaning in terms of flux-force relations of nonequilibrium thermodynamics. Second, within this general thermodynamic frame, the specific treatment of energy transformations of chemical reactions is introduced, with particular emphasis on open systems with internal transformation and external transfer of matter. Third, the chemical transformations in ATP turnover and internal efficiencies of coupled reactions are analyzed in two parts. On the one hand, the enthalpy efficiency is relevant in the context of biological calorimetry in relation to uncoupling and the integration of aerobic and anaerobic metabolism. On the other hand, the molar Gibbs energy efficiency relates to the driving force of coupled reactions and to the control of flux. High metabolic power and maximum efficiency are mutually exclusive. Finally, the discussion of various expressions of efficiency in biological growth requires a careful distinction between energy conservation in transformations (chemical reactions) and energy acquisition in coupled transformation and transfer of energy in the form of externally supplied matter. Better understanding and management of biological resource utilization requires this combined analysis of efficiency in biological energetics.is of efficiency in biological energetics.)
Lotkova 2009 Acta Vet Brno + (Acetaminophen (AAP) overdose causes severe … Acetaminophen (AAP) overdose causes severe liver injury and is the leading cause of acute liver injury in humans. The mechanisms participating in its toxic effect are glutathione depletion, oxidative stress and mitochondrial dysfunction. S-adenosylmethionine (SAMe) is the principal biological methyl donor and is also a precursor of glutathione. In our previous studies we have documented a protective action of SAMe against various toxic injuries of rat hepatocytes in primary cultures. The aim of this study was to evaluate a possible protective effect of SAMe against AAP-induced toxic injury of primary rat hepatocytes. Hepatocytes were exposed to AAP (2.5 mM) or AAP together with SAMe at the final concentrations of 5, 25 or 50 mg/l for 24 h. Incubation of hepatocytes with AAP caused a significant increase of the leakage of lactate dehydrogenase (LDH) (p < 0.001) and decline of the activity of cellular dehydrogenases (WST- 1) (p < 0.001). Co-incubation of hepatocytes with SAMe at any dose did not improve these markers of cellular integrity. The functional indicators improved in hepatocytes co-cultured with SAMe - urea production was significantly increased when using the highest dose of SAMe (p < 0.05); albumin synthesis was higher in all cultured hepatocytes exposed to SAMe (p < 0.05). SAMe did not influence AAP-induced decrease of cellular content of glutathione. Mitochondrial respiration of harvested digitonin-permeabilized hepatocytes was measured; Complex II was more sensitive to toxic action of AAP, respiration was decreased by 20%. This decrease was completely abolished by SAMe.y 20%. This decrease was completely abolished by SAMe.)

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Vrbova 2015 Abstract MiPschool London 2015 + (Acetaminophen (APAP) belongs to the most u … Acetaminophen (APAP) belongs to the most used analgetic and antipyretic drugs. APAP overdose causes liver injury and that is why it is the most frequent cause of acute liver injuries in the Western countries. In some cases, it is also associated with renal impairment occurring with frequency 1-2% of patients with acetaminophen overdose [1,2]. Acetaminophen is detoxified by three major pathways, glucuronidation, sulfation and oxidation by cytochrome P450. At therapeutic doses, a small portion of APAP dose is oxidized by cytochrome P450 to a reactive electrophilic molecule (NAPQI). After overdose, APAP is metabolized predominantly through the oxidation pathway and production of the oxidation product is enhanced. NAPQI is considered to be the toxic metabolite causing cell impairment [3]. However, based on our preliminary results, we postulated, that another metabolite could also cause toxicity.Our study's aim was to characterize the toxicity of APAP metabolite in the human HK-2 cell line. We used a range of concentrations (10-5 mM) to examine the toxicity in cells. We evaluated the toxicity using the detection of mitochondrial dehydrogenase activity (WST-1 test), lactate dehydrogenase activity assay and detection of intracellular ROS production. We observed moderate impairment of cells already after 3 h of treatment based on the finding of decreased mitochondrial dehydrogenase activity in all tested concentrations. After 24 hours, the results showed significant cellular impairment and increased ROS production at all tested concentrations. In conclusion, we have proven our hypothesis that APAP metabolites ought to be also concerned in APAP toxicity. The toxic effect is presumably apparent as a decrease in mitochondrial dehydrogenase activity and induction of ROS production. activity and induction of ROS production.)
Kucera 2016 Drug Chem Toxicol + (Acetaminophen (APAP) hepatotoxicity is oft … Acetaminophen (APAP) hepatotoxicity is often studied in primary cultures of hepatocytes of various species, but there are only few works comparing interspecies differences in susceptibility of hepatocytes to APAP ''in vitro''.The aim of our work was to compare hepatotoxicity of APAP in rat and mouse hepatocytes in primary cultures.Hepatocytes isolated from male Wistar rats and C57Bl/6J mice were exposed to APAP for up to 24 h. We determined lactate dehydrogenase (LDH) activity in culture medium, activity of cellular dehydrogenases (WST-1) and activity of caspases 3 in cell lysate as markers of cell damage/death. We assessed content of intracellular reduced glutathione, production of reactive oxygen species (ROS) and malondialdehyde (MDA). Respiration of digitonin-permeabilized hepatocytes was measured by high resolution respirometry and mitochondrial membrane potential (MMP) was visualized (JC-1).APAP from concentrations of 2.5 and 0.75 mmol/L induced a decrease in viability of rat (p < 0.001) and mouse (p < 0.001) hepatocytes (WST-1), respectively. In contrast to rat hepatocytes, there was no activation of caspase-3 in mouse hepatocytes after APAP treatment. Earlier damage to plasma membrane and faster depletion of reduced glutathione were detected in mouse hepatocytes. Mouse hepatocytes showed increased glutamate + malate-driven respiration in state 4 and higher susceptibility of the outer mitochondrial membrane (OMM) to APAP-induced injury.APAP displayed dose-dependent toxicity in hepatocytes of both species. Mouse hepatocytes in primary culture however had approximately three-fold higher susceptibility to the toxic effect of APAP when compared to rat hepatocytes.effect of APAP when compared to rat hepatocytes.)
Rousarova 2015 Abstract MiPschool London 2015 + (Acetaminophen (APAP) is a frequently used … Acetaminophen (APAP) is a frequently used analgetic and antipyretic drug. After overdose, it may cause a number of pathophysiological processes that can even lead to acute liver and/or kidney failure. The cause of toxicity can be recognized in its metabolic activation but the entire mechanism of acetaminophen toxicity is still unknown. APAP is metabolized in hepatocytes through various pathways. The most important pathway acting in overdose is oxidation of APAP by cytochrome P450 to a substance, which is detoxified by reaction with glutathione [1,2]. We suppose that the metabolite of acetaminophen can also cause toxicity. Thus the main goal of our study was to assess a possible toxic effect of this metabolite in isolated mitochondria using detection of ROS production. We used CM-H2DCFDA molecular probe that is nonfluorescent until oxidized by ROS [3]. We used isolated mitochondria from rat liver and from kidney cells treated with mitochondrial substrates and inhibitors to localize the site of ROS production. We proved that kidney mitochondria and mitochondria from rat liver treated with the acetaminophen metabolite produced ROS in significantly higher extent in comparison with controls. In 5 mM solution, ROS production in mitochondria isolated from rat liver was enhanced 9-fold and 3-fold in presence of glutamate and malate (i.e. complex I-related) and succinate and rotenone (i.e. complex II-related), respectively. Similar results were found in mitochondria isolated from kidney cells. The results support our hypothesis about the possible toxic effect of acetaminophen metabolite likely contributing to the overall toxicity.kely contributing to the overall toxicity.)
Chroeis 2019 Basic Clin Pharmacol Toxicol + (Acetaminophen (APAP) is used worldwide and … Acetaminophen (APAP) is used worldwide and is regarded as safe in therapeutic concentrations but can cause acute liver failure in higher doses. High doses of APAP have been shown to inhibit complex I and II mitochondrial respiratory capacity in mouse hepatocytes, but human studies are lacking. Here, we studied mitochondrial respiratory capacity in human hepatic tissue ''ex vivo'' with increasing doses of APAP. Hepatic biopsies were obtained from 12 obese patients who underwent a Roux-en-Y gastric bypass (RYGB) or a sleeve gastrectomy surgery. Mitochondrial respiration was measured by high-resolution respirometry. Therapeutic concentrations (≤0.13 mmol/L) of APAP did not inhibit state 3 complex I-linked respiration. APAP concentrations of ≥2.0 mmol/L in the medium significantly reduced hepatic mitochondrial respiration in a dose-dependent manner. Complex II-linked mitochondrial respiration was not inhibited by APAP. We conclude that the mitochondrial respiratory capacity is affected by a hepato-toxic effect of APAP, which involved complex I, but not complex II.© 2019 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).(former Nordic Pharmacological Society).)
Piel 2020 PLoS One + (Acetaminophen is one of the most common ov … Acetaminophen is one of the most common over-the-counter pain medications used worldwide and is considered safe at therapeutic dose. However, intentional and unintentional overdose accounts for up to 70 % of acute liver failure cases in the western world. Extensive research has demonstrated that the induction of oxidative stress and mitochondrial dysfunction are central to the development of acetaminophen-induced liver injury. Despite the insight gained on the mechanism of acetaminophen toxicity, there still is only one clinically approved pharmacological treatment option, N-acetylcysteine. N-acetylcysteine increases the cell's antioxidant defense and protects liver cells from further acetaminophen-induced oxidative damage. Because it primarily protects healthy liver cells rather than rescuing the already injured cells alternative treatment strategies that target the latter cell population are warranted. In this study, we investigated mitochondria as therapeutic target for the development of novel treatment strategies for acetaminophen-induced liver injury. Characterization of the mitochondrial toxicity due to acute acetaminophen overdose ''in vitro'' in human cells using detailed respirometric analysis revealed that Complex I-linked (NADH-dependent) but not Complex II-linked (succinate-dependent) mitochondrial respiration is inhibited by acetaminophen. Treatment with a novel cell-permeable succinate prodrug rescues acetaminophen-induced impaired mitochondrial respiration. This suggests cell-permeable succinate prodrugs as a potential alternative treatment strategy to counteract acetaminophen-induced liver injury.teract acetaminophen-induced liver injury.)
Russell 1991 Am J Physiol + (Acetoacetate, when present as the only fue … Acetoacetate, when present as the only fuel for respiration in rat hearts, causes an impairment in contractile function that is reversible with the addition of substrates that can contribute to anaplerosis. To determine the importance of pyruvate carboxylation via NADP(+)-dependent malic enzyme on metabolism and function in hearts oxidizing acetoacetate, isolated working rat hearts were perfused with [1-14C]pyruvate and acetoacetate. While the cardiac power output after 60 min of perfusion in hearts utilizing acetoacetate alone had fallen to 44% of the initial value, the addition of pyruvate resulted in a stable performance with no fall in the work output. When hydroxymalonate, an inhibitor of NADP(+)-dependent malic enzyme and malate dehydrogenase, was added to the two substrates, function at 60 min was similar to the value for hearts oxidizing acetoacetate alone. Measurements of the specific activities of malate, aspartate, and citrate confirm inhibition of both pyruvate carboxylation and malate oxidation. The findings are consistent with a mechanism in which the enrichment of malate by pyruvate improves function by increasing the production of reducing equivalents by the malate dehydrogenase and the isocitrate dehydrogenase reactions increase flux through the span of the tricarboxylic acid cycle from malate to 2-oxoglutarate. The present study demonstrates the physiological importance of anaplerotic pathways in maintaining contractile function in the heart.taining contractile function in the heart.)
Manko 2013 Acta Physiol (Oxf) + (Acetylcholine as one of the main secretago … Acetylcholine as one of the main secretagogues modulates mitochondrial functions in acinar pancreacytes, presumably due to increase in ATP hydrolysis or Ca2+ transport into mitochondria. The aim of this work was to investigate the mechanisms of carbachol (CCh) action on respiration and oxidative phosphorylation of isolated pancreatic acini.Respiration of intact or permeabilized rat pancreatic acini was studied at 37 °C using a Clark oxygen electrode.Respiration rate of isolated acini in rest was 0.27 ± 0.01 nmol O2 s-1 10-6 cells. Addition of 10 μM CCh into respiration chamber evoked biphasic stimulation of respiration. Rapid increase of respiration by 20.1% lasted for approx. 1 min, followed by decrease to level by 11.5% higher than control. Addition of 1 μm CCh caused monophasic increase by 11.5%. Preincubation (5 min) with 1 or 10 μm CCh elevated respiration rate by 12.5 or 11.2% respectively. FCCP prevented the effect of CCh. Preincubation with 1 (but not 10) μm CCh increased FCCP-uncoupled respiration rate. Thapsigargin slightly elevated respiration, but ryanodine did not. Application of 2-aminoethoxydiphenyl borate or ruthenium red prevented the effects of CCh on respiration, while oligomycin abolished them. Preincubation with 1 μm CCh prior to cell permeabilization increased respiration rate at pyruvate+malate oxidation, but not at succinate oxidation. In contrast, preincubation with 10 μm CCh decreased pyruvate+malate oxidation.Medium CCh dose (1 μm) intensifies respiration and oxidative phosphorylation of acinar pancreacytes by feedforward mechanism via Ca2+ transport into mitochondria and activation of Ca2+ /ADP-sensitive mitochondrial dehydrogenases. Prolonged action of high CCh dose (10 μm) might impair mitochondrial functions.ndrial dehydrogenases. Prolonged action of high CCh dose (10 μm) might impair mitochondrial functions.)
Walker 1970 J Biol Chem + (Acid hydrolysis of flavin peptides from th … Acid hydrolysis of flavin peptides from the active center of mammalian succinate dehydrogenase yields a substituted riboflavin which was isolated in pure form. It contains a substituent attached to position 8a of riboflavin. Drastic acid hydrolysis of this compound and catalytic hydrogenation yield nearly 1 mole of free histidine. Histidine is also liberated on neutral photolysis. The presence of histidine is confirmed by behavior on high voltage electrophoresis at various pH values and by acid titration curves. Linkage of the 8cr-CHs group of riboflavin is to one of the imidazole ring nitrogens since neither the flavin peptide nor its acid derivative give a Pauly reaction. This assignment is in full accord with the characteristic pH-fluorescence curve of covalently bound flavin. The pK of the fluorescence quenching agrees with that expected for the imidazole nitrogen in histidyl flavin.the imidazole nitrogen in histidyl flavin.)
Boushel 2011 Mitochondrion + (Across a wide range of species and body ma … Across a wide range of species and body mass a close matching exists between maximal conductive oxygen delivery and mitochondrial respiratory rate. In this study we investigated in humans how closely ''in vivo'' maximal oxygen consumption (''V''O(2)max) is matched to muscle tissue-specific OXPHOS capacity ([[State 3]]) respiration. High-resolution respirometry was used to quantify mitochondrial respiration from the biopsies of arm and leg muscles while ''in vivo'' arm and leg ''V''O(2) were determined by the Fick method during leg cycling and arm cranking. We hypothesized that muscle mitochondrial respiratory rate exceeds that of systemic oxygen delivery. OXPHOS capacity of the deltoid muscle (4.3±0.4 mmol O(2)kg(-1)min(-1)) was similar to the ''in vivo'' ''V''O(2) during maximal arm cranking (4.7±0.5 mmol O(2)kg(-1)min(-1)) with 6 kg muscle. In contrast, the mitochondrial OXPHOS capacity of the quadriceps was 6.9±0.5 mmol O(2)kg(-1)min(-1), exceeding the ''in vivo'' leg ''V''O(2)max (5.0±0.2mmolO(2)kg(-1)min(-1)) during leg cycling with 20 kg muscle (''P''<0.05). Thus, when half or more of the body muscle mass is engaged during exercise, muscle mitochondrial respiratory capacity surpasses ''in vivo'' ''V''O(2)max. The findings reveal an excess capacity of muscle mitochondrial respiratory rate over O(2) delivery by the circulation in the cascade defining maximal oxidative rate in humans.de defining maximal oxidative rate in humans.)
Mills 2016 Cell + (Activated macrophages undergo metabolic re … Activated macrophages undergo metabolic reprogramming, which drives their pro-inflammatory phenotype, but the mechanistic basis for this remains obscure. Here, we demonstrate that upon lipopolysaccharide (LPS) stimulation, macrophages shift from producing ATP by oxidative phosphorylation to glycolysis while also increasing succinate levels. We show that increased mitochondrial oxidation of succinate via succinate dehydrogenase (SDH) and an elevation of mitochondrial membrane potential combine to drive mitochondrial reactive oxygen species (ROS) production. RNA sequencing reveals that this combination induces a pro-inflammatory gene expression profile, while an inhibitor of succinate oxidation, dimethyl malonate (DMM), promotes an anti-inflammatory outcome. Blocking ROS production with rotenone by uncoupling mitochondria or by expressing the alternative oxidase (AOX) inhibits this inflammatory phenotype, with AOX protecting mice from LPS lethality. The metabolic alterations that occur upon activation of macrophages therefore repurpose mitochondria from ATP synthesis to ROS production in order to promote a pro-inflammatory state.order to promote a pro-inflammatory state.)
Droese 2006 J Biol Chem + (Activation by diazoxide and inhibition by … Activation by diazoxide and inhibition by 5-hydroxydecanoate are the hallmarks of mitochondrial ATP-sensitive K+(KATP) channels. Opening of these channels is thought to trigger cytoprotection (preconditioning) through the generation of reactive oxygen species. However, we found that diazoxide-induced oxidation of the widely used reactive oxygen species indicator 2′,7′-dichlorodihydrofluorescein in isolated liver and heart mitochondria was observed in the absence of ATP or K+ and therefore independent of KATP channels. The response was blocked by stigmatellin, implying a role for the cytochrome ''bc''1 complex (Complex III). Diazoxide, though, did not increase hydrogen peroxide (H2O2) production (quantitatively measured with Amplex Red) in intact mitochondria, submitochondrial particles, or purified cytochrome ''bc''1 complex. We confirmed that diazoxide inhibited succinate oxidation, but it also weakly stimulated State 4 respiration even in K+-free buffer, excluding a role for KATP channels. Furthermore, we have shown previously that 5-hydroxydecanoate is partially metabolized, and we hypothesized that fatty acid metabolism may explain the ability of this putative mitochondrial KATP channel blocker to inhibit diazoxide-induced flavoprotein fluorescence, commonly used as an assay of KATP channel activity. Indeed, consistent with our hypothesis, we found that decanoate inhibited diazoxide-induced flavoprotein oxidation. Taken together, our data question the “mitochondrial KATP channel” hypothesis of preconditioning. Diazoxide did not evoke superoxide (which dismutates to H2O2) from the respiratory chain by a direct mechanism, and the stimulatory effects of this compound on mitochondrial respiration and 2′,7′-dichlorodihydrofluorescein oxidation were not due to the opening of KATP channels.the respiratory chain by a direct mechanism, and the stimulatory effects of this compound on mitochondrial respiration and 2′,7′-dichlorodihydrofluorescein oxidation were not due to the opening of KATP channels.)
Bernhardt 2015 Abstract MiPschool Greenville 2015 + (Activation of mammalian embryonic developm … Activation of mammalian embryonic development relies on a series of fertilization-induced increases in intracellular Ca2+. Full egg activation also requires influx of extracellular Ca2+, but the channel or channels mediating this influx remain unknown. In these studies we examined whether T-type Ca2+ channels, including CACNA1H subunit-containing CaV3.2 channels, mediate Ca2+ entry after fertilization. We found that female mice lacking CACNA1H have reduced litter size. Careful analysis of Ca2+ oscillation patterns following ''in vitro'' fertilization (IVF) of ''Cacna1h-/-'' eggs revealed shortening of the first Ca2+ transient length and reduction in Ca2+ oscillation persistence. Both total and endoplasmic reticulum (ER) Ca2+ stores in ''Cacna1h-/-'' eggs were reduced, showing an impairment of Ca2+ accumulation during oocyte maturation in ''Cacna1h-/-'' eggs. Pharmacological inhibition of T-type channels during ''in vitro'' maturation also reduced Ca2+ store accumulation, indicating that T-type channels are responsible for mediating Ca2+ entry and ER store accumulation during meiotic maturation. T-type channel inhibition also reduced oscillation persistence, frequency, and duration following IVF in wild-type eggs. Together, these data support previously unrecognized roles for T-type Ca2+ channels in mediating the maturation-associated increase in ER Ca2+ stores and allowing Ca2+ influx required for the activation of embryo development. In future studies, we plan to investigate how fluxes in oocyte Ca2+ and Zn2+ influence mitochondrial function, which is a critical determinant of oocyte and embryo quality. Developing better understanding of the interplay between these pathways may translate into clinical application to improve assisted reproductive technologies.;2+ influence mitochondrial function, which is a critical determinant of oocyte and embryo quality. Developing better understanding of the interplay between these pathways may translate into clinical application to improve assisted reproductive technologies.)
Svensson 2017 Acta Physiol (Oxf) + (Activation of the NAD+</sup& … Activation of the NAD+ dependent protein deacetylase SIRT1 has been proposed as a therapeutic strategy to treat mitochondrial dysfunction and insulin resistance in skeletal muscle. However, lifelong overexpression of SIRT1 in skeletal muscle does not improve parameters of mitochondrial function and insulin sensitivity. In this study, we investigated whether temporal overexpression of SIRT1 in muscle of adult mice would affect skeletal muscle mitochondrial function and insulin sensitivity.To circumvent potential effects of germline SIRT1 overexpression, we utilized an inducible model of SIRT1 overexpression in skeletal muscle of adult mice (i-mOX). Insulin sensitivity was assessed by 2-deoxyglucose uptake, muscle maximal respiratory function by high-resolution respirometry and systemic energy expenditure was assessed by whole body calorimetry.Although SIRT1 was highly, and specifically, overexpressed in skeletal muscle of i-mOX compared to WT mice, glucose tolerance and skeletal muscle insulin sensitivity were comparable between genotypes. Additionally, markers of mitochondrial biogenesis, muscle maximal respiratory function and whole-body oxygen consumption were also unaffected by SIRT1 overexpression.These results support previous work demonstrating that induction of SIRT1 in skeletal muscle, either at birth or in adulthood, does not impact muscle insulin action or mitochondrial function.© 2017 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.iological Society. Published by John Wiley & Sons Ltd.)
Magga 2019 Mol Ther + (Activin A and myostatin, members of the tr … Activin A and myostatin, members of the transforming growth factor (TGF)-β superfamily of secreted factors, are potent negative regulators of muscle growth, but their contribution to myocardial ischemia-reperfusion (IR) injury is not known. The aim of this study was to investigate if activin 2B (ACVR2B) receptor ligands contribute to myocardial IR injury. Mice were treated with soluble ACVR2B decoy receptor (ACVR2B-Fc) and subjected to myocardial ischemia followed by reperfusion for 6 or 24 h. Systemic blockade of ACVR2B ligands by ACVR2B-Fc was protective against cardiac IR injury, as evidenced by reduced infarcted area, apoptosis, and autophagy and better preserved LV systolic function following IR. ACVR2B-Fc modified cardiac metabolism, LV mitochondrial respiration, as well as cardiac phenotype toward physiological hypertrophy. Similar to its protective role in IR injury ''in vivo'', ACVR2B-Fc antagonized SMAD2 signaling and cell death in cardiomyocytes that were subjected to hypoxic stress. ACVR2B ligand myostatin was found to exacerbate hypoxic stress. In addition to acute cardioprotection in ischemia, ACVR2B-Fc provided beneficial effects on cardiac function in prolonged cardiac stress in cardiotoxicity model. By blocking myostatin, ACVR2B-Fc potentially reduces cardiomyocyte death and modifies cardiomyocyte metabolism for hypoxic conditions to protect the heart from IR injury.tions to protect the heart from IR injury.)
Benard 2008 Int J Biochem Cell Biol + (Activity defects in respiratory chain comp … Activity defects in respiratory chain complexes are responsible for a large variety of pathological situations, including neuromuscular diseases and multisystemic disorders. Their impact on energy production is highly variable and disproportional. The same biochemical or genetic defect can lead to large differences in clinical symptoms and severity between tissues and patients, making the pathophysiological analysis of mitochondrial diseases difficult. The existence of compensatory mechanisms operating at the level of the respiratory chain might be an explanation for the biochemical complexity observed for respiratory defects. Here, we analyzed the role of cytochrome c and coenzyme Q in the attenuation of complex III and complex IV pharmacological inhibition on the respiratory flux. Spectrophotometry, HPLC-EC, polarography and enzymology permitted the calculation of molar ratios between respiratory chain components, giving values of 0.8:61:3:12:6.8 in muscle and 1:131:3:9:6.5 in liver, for CII:CoQ:CIII:Cyt c:CIV. The results demonstrate the dynamic functional compartmentalization of respiratory chain substrates, with the existence of a substrate pool that can be recruited to maintain energy production at normal levels when respiratory chain complexes are inhibited. The size of this reserve was different between muscle and liver, and in proportion to the magnitude of attenuation of each respiratory defect. Such functional compartmentalization could result from the recently observed physical compartmentalization of respiratory chain substrates. The dynamic nature of the mitochondrial network may modulate this compartmentalization and could play a new role in the control of mitochondrial respiration as well as apoptosis.hondrial respiration as well as apoptosis.)
Soendergaard 2016 Eur J Sport Sci + (Actovegin, a deproteinized haemodialysate … Actovegin, a deproteinized haemodialysate of calf blood, is suggested to have ergogenic properties, but this potential effect has never been investigated in human skeletal muscle. To investigate this purported ergogenic effect, we measured the mitochondrial respiratory capacity in permeabilized human skeletal muscle fibres acutely exposed to Actovegin in a low and in a high dose. We found that Actovegin, in the presence of complex I-linked substrates increased the oxidative phosphorylation (OXPHOS) capacity significantly in a concentration-dependent manner (19 ± 3, 31 ± 4 and 45 ± 4 pmol/mg/s). Maximal OXPHOS capacity with complex I and II-linked substrate was increased when the fibres were exposed to the high dose of Actovegin (62 ± 6 and 77 ± 6 pmol/mg/s) (''p ''< .05). The respiratory capacity of the electron transfer-pathway as well as Vmax and Km were also increased in a concentration-dependent manner after Actovegin exposure (70 ± 6, 79 ± 6 and 88 ± 7 pmol/mg/s; 13 ± 2, 25 ± 3 and 37 ± 4 pmol/mg/s; 0.08 ± 0.02, 0.21 ± 0.03 and 0.36 ± 0.03 mM, respectively) (''p'' < .05). In summary, we report for the first time that Actovegin has a marked effect on mitochondrial oxidative function in human skeletal muscle. Mitochondrial adaptations like this are also seen after a training program in human subjects. Whether this improvement translates into an ergogenic effect in athletes and thus reiterates the need to include Actovegin on the World Anti-Doping Agency's active list remains to be investigated.Agency's active list remains to be investigated.)
Soendergaard 2016 Abstract IOC109 + (Actovegin, a drug made from the deproteini … Actovegin, a drug made from the deproteinized hemodialysate of calf blood increases the mitochondrial respiratory capacity of untrained and overweight subjects, indicating that Actovegin may have the potential to improve performance. These findings are interesting because the drug is not on the World Anti-Doping Agency’s prohibited list, but used by athletes. Therefore, we wanted to investigate whether Actovegin had the same effect in trained subjects. Also, we wanted to compare the effect of Actovegin with the effect of erythropoietin (EPO; a banned substance) on the mitochondrial respiratory capacity. We obtained basal muscle biopsies (''m. vastus lateralis'') from 8 trained subjects (VO2max: 54±2ml/min/kg). The skeletal muscle fibers were acutely exposed to either Actovegin (50µl/ml) or EPO (50µl/ml, 2000IU) during permeabilization, washing of the fibers and the respiratory analysis, resulting in a ~2h exposure time. Mitochondrial respiratory capacity was measured with high-resolution respirometry (Oxygraph-2k; Oroboros , Innsbruck, Austria) and by sequential addition of malate, glutamate, ADP, succinate and FCCP.EPO and Actovegin increased maximal complex I activity (''P''<0.05) compared to control (22±4, 43±3, 61±5pmol/mg/s) with a significant difference between EPO and Actovegin (43±3, 61±5pmol/mg/s, respectively). Only Actovegin increased the maximal oxidative phosphorylation capacity significantly (72±5, 82±8, 95±4pmol/mg/s), but both EPO and Actovegin increased the maximal electron transport system capacity (77±5, 101±9, 112±10pmol/mg/s) (''P''<0.05). In regards to ADP kinetics, Vmax was significantly increased by EPO and Actovegin (18±2, 33±3, 50±4pmol/mg/s) (''P''<0.05), whereas Km was unaltered by EPO, but significantly increased by Actovegin (0.18±0.04, 0.21±0.04, 0.72±0.31mM).The study demonstrates that acute exposure of human muscle fibers to EPO or Actovegin increases the mitochondrial respiratory capacity of trained subjects. The mechanism(s) are not clear, but EPO has been found to increase the NAD+ levels and the NAD+/NADH ratio in myoblasts (1), which could explain the observed increased complex I respiration with EPO (2). Actovegin contains succinate which in part can explain the effect of Actovegin on the mitochondrial respiration. It is not known whether Actovegin also contains NAD+, but it is intriguing to think that Actovegin and EPO might modulate mitochondrial function through the same mechanism, but this is only speculations. the same mechanism, but this is only speculations.)
Arias-Mayenco 2018 Cell Metab + (Acute O2 sensing by … Acute O2 sensing by peripheral chemoreceptors is essential for mammalian homeostasis. Carotid body glomus cells contain O2-sensitive ion channels, which trigger fast adaptive cardiorespiratory reflexes in response to hypoxia. O2-sensitive cells have unique metabolic characteristics that favor the hypoxic generation of mitochondrial complex I (MCI) signaling molecules, NADH and reactive oxygen species (ROS), which modulate membrane ion channels. We show that responsiveness to hypoxia progressively disappears after inducible deletion of the Ndufs2 gene, which encodes the 49 kDa subunit forming the coenzyme Q binding site in MCI, even in the presence of MCII substrates and chemical NAD+ regeneration. We also show contrasting effects of physiological hypoxia on mitochondrial ROS production (increased in the intermembrane space and decreased in the matrix) and a marked effect of succinate dehydrogenase activity on acute O2 sensing. Our results suggest that acute responsiveness to hypoxia depends on coenzyme QH2/Q ratio-controlled ROS production in MCI.esponsiveness to hypoxia depends on coenzyme QH2/Q ratio-controlled ROS production in MCI.)
Stampley 2023 Physiol Rep + (Acute aerobic exercise increases the numbe … Acute aerobic exercise increases the number and proportions of circulating peripheral blood mononuclear cells (PMBC) and can alter PBMC mitochondrial bioenergetics. In this study, we aimed to examine the impact of a maximal exercise bout on immune cell metabolism in collegiate swimmers. Eleven (7 M/4F) collegiate swimmers completed a maximal exercise test to measure anaerobic power and capacity. Pre- and postexercise PBMCs were isolated to measure the immune cell phenotypes and mitochondrial bioenergetics using flow cytometry and high-resolution respirometry. The maximal exercise bout increased circulating levels of PBMCs, particularly in central memory (KLRG1+/CD57-) and senescent (KLRG1+/CD57+) CD8+ T cells, whether measured as a % of PMBCs or as absolute concentrations (all p < 0.05). At the cellularlevel, the routine oxygen flow (IO2 [pmol·s-1 ·106 PBMCs-1 ]) increased following maximal exercise (p = 0.042); however, there were no effects of exercise on the IO2 measured under the LEAK, oxidative phosphorylation (OXPHOS), or electron transfer (ET) capacities. There were exercise-induced increases in the tissue-level oxygen flow (IO2-tissue [pmol·s-1 ·mL blood-1 ]) for all respiratory states (all p < 0.01), except for the LEAK state, after accounting for the mobilization of PBMCs. Future subtype-specific studies are needed to characterize further maximal exercise's true impact on immune cell bioenergetics.zation of PBMCs. Future subtype-specific studies are needed to characterize further maximal exercise's true impact on immune cell bioenergetics.)
Holsgrove 2019 Thesis + (Acute changes in temperature have a signif … Acute changes in temperature have a significant impact on ectotherm metabolic function due to their inability to regulate internal temperatures. An alteration of metabolic rate will drive modulations in cardiac function in order to meet the changing oxygen demands of aerobically active tissues. The function of the fish heart therefore underpins an organisms ability to survive changing temperature. There have been multiple studies assessing the effects of temperature on the metabolism of fish tissue systems but relatively few on the heart. As such, the aims of this thesis were to study the effects of cooling and warming on cardiac metabolism of the rainbow trout. As mitochondria are responsible for producing the majority of ATP for cardiomyocytes and drive aerobic demand, the experiments in this thesis centred on the mitochondrial response to temperature change. In chapter 3, I provide the first thorough investigation into the effect of cold and warm acclimation on cardiac mitochondria morphology in fish. Cold acclimation induced mitochondrial proliferation and an upregulation of mitochondrial fusion, whilst warm acclimation did not increase mitochondrial content but is suggested to increase fission events. A lack of change in internal mitochondrial ultrastructure however doesn't suggest any change in energetic capacity. In chapter 4, I demonstrate that mitochondria are sensitive to acute temperature changes, although their response did not fit expectations. Cold acclimated mitochondria decreased respiratory rates when acutely warmed whilst acute cooling caused an increase in mitochondrial function in warm acclimated fish. This acute response demonstrated a narrowing of the thermal performance window in the cold acclimated fish with warm acclimation shifting the thermal optimum and lowering upper thermal limits. This repression of mitochondrial function may have a significant impact on rainbow trout fitness if exposed to changing temperatures. We found that ROS production was insensitive to temperature changes which may be a result of complex I and III remodelling or due to changes in antioxidant capacity. Metabolic enzymes from the TCA cycle, electron transport chain and fatty acid oxidation pathways demonstrated a limited capacity for remodelling following temperature changes. We show that cold acclimation sensitised metabolic enzymes to acute changes in temperature whilst warm acclimation induced a desensitisation. Cold acclimation did not induce a switch to fatty acid metabolism as might be expected and we demonstrated that citrate synthase is a poor biomarker for mitochondrial content in the rainbow trout heart. Overall, I have shown that the fish heart is sensitive to thermal changes which are reflected functionally and morphologically. Despite being sensitive to temperature changes rainbow trout mitochondria do not fi t traditional compensatory remodelling patterns and instead shift thermal optima. Cold acclimation leads a thermal sensitisation of metabolic enzymes which is not seen in the warm which displayed generally high metabolic activities. This metabolic remodelling may prove to be energetically costly and possibly detrimental to organismal fitness in the wild.imental to organismal fitness in the wild.)
Johansen 2019 Comp Biochem Physiol C Toxicol Pharmacol + (Acute exposure to crude oil and polycyclic … Acute exposure to crude oil and polycyclic aromatic hydrocarbons (PAH) can severely impair cardiorespiratory function and swim performance of larval, juvenile and adult fish. Interestingly, recent work has documented an oil induced decoupling of swim performance (Ucrit) and maximum metabolic rate (MMR) whereby oil causes a decline in Ucrit without a parallel reduction in MMR. We hypothesize that this uncoupling is due to impaired mitochondrial function in swimming muscles that results in increased proton leak, and thus less ATP generated per unit oxygen. Using high resolution mitochondrial respirometry, we assessed 11 metrics of mitochondrial performance in red and cardiac muscle from permeabilized fibers isolated from red drum following control or 24 h crude oil (high energy water accommodated fractions) exposure. Two experimental series were performed, a Deepwater Horizon relevant low dose (29.6 ± 7.4 μg L-1 ∑PAH50) and a proof-of-concept high dose (64.5 ± 8.9 μg L-1 ∑PAH50). No effects were observed on any mitochondrial parameter in either tissue at the low oil dose; however, high dose exposure provided evidence of impairment in the OXPHOS respiratory control ratio and OXPHOS spare capacity in red muscle following oil exposure, as well as a shift from Complex I to Complex II during OXPHOS respiration. No effects of the high dose oil treatment were observed in cardiac muscle. As such, mitochondrial dysfunction is unlikely to be the underlying mechanism for decoupling of Ucrit and MMR following acute oil exposure in red drum. Furthermore, mitochondrial dysfunction does not appear to be a relevant toxicological impairment in juvenile red drum with respect to the Deepwater Horizon oil spill, although impairments may be observed under higher dose exposure scenarios.Copyright © 2019 Elsevier Inc. All rights reserved. 2019 Elsevier Inc. All rights reserved.)
Banh 2015 Comp Biochem Physiol B Biochem Mol Biol + (Acute heat challenge is known to induce ce … Acute heat challenge is known to induce cell-level oxidative stress in fishes. Mitochondria are well known for the capacity to make reactive oxygen species (ROS) and as such are often implicated as a source of the oxidants associated with this thermally-induced oxidative stress. This implication is often asserted, despite little direct data for mitochondrial ROS metabolism in fishes. Here we characterize mitochondrial ROS metabolism in three Actinopterygian fish species at two levels, the capacity for superoxide/H2O2 production and the antioxidant thiol-reductase enzyme activities. We find that red muscle mitochondria from all three species have measurable ROS production and respond to different assay conditions consistent with what might be anticipated; assuming similar relative contributions from difference ROS producing sites as found in rat skeletal muscle mitochondria. Although there are species and assay specific exceptions, fish mitochondria may have a greater capacity to produce ROS than that found in the rat when either normalized to respiratory capacity or determined at a common assay temperature. The interspecific differences in ROS production are not correlated with thiol-based antioxidant reductase activities. Moreover, mimicking an acute ''in vivo'' heat stress by comparing the impact of increasing assay temperature on these processes in vitro, we find evidence supporting a preferential activation of mitochondrial H2O2 production relative to the increase in the capacity of reductase enzymes to supply electrons to the mitochondrial matrix peroxidases. This supports the contention that mitochondria may be, at least in part, responsible for the ROS that lead to oxidative stress in fish tissues exposed to acute heat challenge.for the ROS that lead to oxidative stress in fish tissues exposed to acute heat challenge.)
Calbet 2003 Am J Physiol Regul Integr Comp Physiol + (Acute hypoxia (AH) reduces maximal O<su … Acute hypoxia (AH) reduces maximal O2 consumption (''V''O2max), but after acclimatization, and despite increases in both hemoglobin concentration and arterial O2 saturation that can normalize arterial O2 concentration ([O2]), ''V''O2max remains low. To determine why, seven lowlanders were studied at ''V''O2max (cycle ergometry) at sea level (SL), after 9-10 wk at 5260 m [chronic hypoxia (CH)], and 6 mo later at SL in AH (''F''iO2 = 0.105) equivalent to 5260 m. Pulmonary and leg indexes of O2 transport were measured in each condition. Both cardiac output and leg blood flow were reduced by approximately 15 % in both AH and CH (''P'' < 0.05). At maximal exercise, arterial [O2] in AH was 31 % lower than at SL (''P'' < 0.05), whereas in CH it was the same as at SL due to both polycythemia and hyperventilation. O2 extraction by the legs, however, remained at SL values in both AH and CH. Although at both SL and in AH, 76 % of the cardiac output perfused the legs, in CH the legs received only 67 %. Pulmonary ''V''O2max (4.1 +/- 0.3 L/min at SL) fell to 2.2 +/- 0.1 L/min in AH (''P'' < 0.05) and was only 2.4 +/- 0.2 L/min in CH (''P'' < 0.05). These data suggest that the failure to recover ''V''O2max after acclimatization despite normalization of arterial [O2] is explained by two circulatory effects of altitude: 1) failure of cardiac output to normalize and 2) preferential redistribution of cardiac output to nonexercising tissues. Oxygen transport from blood to muscle mitochondria, on the other hand, appears unaffected by CH.t;sub>2] is explained by two circulatory effects of altitude: 1) failure of cardiac output to normalize and 2) preferential redistribution of cardiac output to nonexercising tissues. Oxygen transport from blood to muscle mitochondria, on the other hand, appears unaffected by CH.)
Wu 2007 Am J Physiol Lung Cell Mol Physiol + (Acute hypoxia causes pulmonary vasoconstri … Acute hypoxia causes pulmonary vasoconstriction and coronary vasodilation. The divergent effects of hypoxia on pulmonary and coronary vascular smooth muscle cells suggest that the mechanisms involved in oxygen sensing and downstream effectors are different in these two types of cells. Since production of reactive oxygen species (ROS) is regulated by oxygen tension, ROS have been hypothesized to be a signaling mechanism in hypoxia-induced pulmonary vasoconstriction and vascular remodeling. Furthermore, an increased ROS production is also implicated in arteriosclerosis. In this study, we determined and compared the effects of hypoxia on ROS levels in human pulmonary arterial smooth muscle cells (PASMC) and coronary arterial smooth muscle cells (CASMC). Our results indicated that acute exposure to hypoxia (Po(2) = 25-30 mmHg for 5-10 min) significantly and rapidly decreased ROS levels in both PASMC and CASMC. However, chronic exposure to hypoxia (Po(2) = 30 mmHg for 48 h) markedly increased ROS levels in PASMC, but decreased ROS production in CASMC. Furthermore, chronic treatment with endothelin-1, a potent vasoconstrictor and mitogen, caused a significant increase in ROS production in both PASMC and CASMC. The inhibitory effect of acute hypoxia on ROS production in PASMC was also accelerated in cells chronically treated with endothelin-1. While the decreased ROS in PASMC and CASMC after acute exposure to hypoxia may reflect the lower level of oxygen substrate available for ROS production, the increased ROS production in PASMC during chronic hypoxia may reflect a pathophysiological response unique to the pulmonary vasculature that contributes to the development of pulmonary vascular remodeling in patients with hypoxia-associated pulmonary hypertension.hypoxia-associated pulmonary hypertension.)
Cortes 2023 Nat Commun + (Acute inflammation can either resolve thro … Acute inflammation can either resolve through immunosuppression or persist, leading to chronic inflammation. These transitions are driven by distinct molecular and metabolic reprogramming of immune cells. The anti-diabetic drug Metformin inhibits acute and chronic inflammation through mechanisms still not fully understood. Here, we report that the anti-inflammatory and reactive-oxygen-species-inhibiting effects of Metformin depend on the expression of the plasticity factor ZEB1 in macrophages. Using mice lacking Zeb1 in their myeloid cells and human patient samples, we show that ZEB1 plays a dual role, being essential in both initiating and resolving inflammation by inducing macrophages to transition into an immunosuppressed state. ZEB1 mediates these diverging effects in inflammation and immunosuppression by modulating mitochondrial content through activation of autophagy and inhibition of mitochondrial protein translation. During the transition from inflammation to immunosuppression, Metformin mimics the metabolic reprogramming of myeloid cells induced by ZEB1. Mechanistically, in immunosuppression, ZEB1 inhibits amino acid uptake, leading to downregulation of mTORC1 signalling and a decrease in mitochondrial translation in macrophages. These results identify ZEB1 as a driver of myeloid cell metabolic plasticity, suggesting that targeting its expression and function could serve as a strategy to modulate dysregulated inflammation and immunosuppression.ulated inflammation and immunosuppression.)