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Wang 2019 Free Radic Biol Med + (Although insulin-like growth factor-1 rece … Although insulin-like growth factor-1 receptor (IGF-1R) has been accepted as a major determinant of cancers, its biological roles and corresponding mechanisms in tumorigenesis have remained elusive. Herein, we demonstrate that IGF-1R plays pivotal roles in the regulation of mitochondrial respiratory chain and functions during colitis and tumorigenesis. Heterozygous knockout IGF-1R attenuated azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colitis and colitis associated cancer (CAC) in Igf1r+/- mice. Heterozygous knockout IGF-1R confers resistance to oxidative stress-induced damage on colorectal epithelial cells by protecting mitochondrial dynamics and structures. IGF-1R low expression improves the biological function of mitochondrial fusion under oxidative stress. Mechanically, an increase in respiratory coupling index (RCI) and oxidative phosphorylation index (ADP/O) was seen in colorectal epithelial cells of Igf1r+/- mice. Seahorse XFe-24 analyzer analysis of mitochondrial bioenergetics demonstrated an increase in oxygen consumption rate (OCR) and a decrease of extracellular acidification rate (ECAR) in Igf1r+/- cells. Further analysis suggests the protection mechanisms of Igf1r+/- cells from oxidative stress through the activation of the mitochondrial respiratory chain and LKB1/AMPK pathways. These results highlight the biological roles of IGF-1R at the nexus between oxidative damage and mitochondrial function and a connection between colitis and colorectal cancer.Copyright © 2019 Elsevier Inc. All rights reserved.een colitis and colorectal cancer. Copyright © 2019 Elsevier Inc. All rights reserved.)
Marchi 2014 J Physiol + (Although it has long been known that mitoc … Although it has long been known that mitochondria take up Ca2+, the molecular identities of the channels and transporters involved in this process were revealed only recently. Here, we discuss the recent work that has led to the characterization of the mitochondrial calcium uniporter complex, which includes the channel-forming subunit MCU (mitochondrial calcium uniporter) and its regulators MICU1, MICU2, MCUb, EMRE, MCUR1 and miR-25. We review not only the biochemical identities and structures of the proteins required for mitochondrial Ca2+ uptake but also their implications in different physiopathological contexts. in different physiopathological contexts.)
Cai 2021 Free Radic Biol Med + (Although it is well known that selective i … Although it is well known that selective intra-arterial cooling (SI-AC) elicits cerebral protection against ischemia/reperfusion (I/R) injury, the underlying mechanism remains unclear. This study aimed to determine whether SI-AC can protect against cerebral I/R injury by inhibiting oxidative stress and mitochondrial dysfunction through regulation of Sirt3 deSUMOylation via SENP1.All mice were subjected to 2 h of cerebral ischemia followed by 24 h of reperfusion. SI-AC treatment was performed by infusion with cold saline (10 °C, 20 mL/kg) for 15 min through a microcatheter placed in the internal carotid artery immediately before reperfusion. The infarct volume, survival rate, neurological deficit scores, behavioral parameters, histopathology findings, and apoptosis were assessed. HT22 cells were subjected to 2 h of oxygen and sugar deprivation (OGD) and 22 h of reoxygenation. HA-SUMO1, Flag-Sirt3, a Sirt3 mutation plasmid (Flag-Sirt3 K288R), His-SENP1, and SENP1 small interfering RNA were transfected into HT22 cells 48 h before OGD. Apoptosis-related proteins were analyzed by western blotting. SUMOylation of Sirt3, acetylation of cyclooxygenase 1 (COX1), superoxide dismutase 2 (SOD2), and isocitrate dehydrogenase 2 (IDH2), the activities of COX1, SOD2, and IDH2, oxidative stress, and mitochondrial dysfunction were evaluated.Compared with the I/R group, SI-AC decreased cerebral infarct volume and neurological deficit scores and increased motor coordination, exploratory behavior, and memory. Hematoxylin and eosin and Nissl staining showed that SI-CA decreased karyopyknosis, nuclear fragmentation, and nucleolysis, increased neuron density, and decreased the cell apoptosis rate. In addition, Sirt3 was revealed as a target protein of SUMO1. SI-AC attenuated cerebral I/R injury through Sirt3 deSUMOylation via SENP1.SENP1-mediated deSUMOylation of Sirt3 plays an essential role in SI-AC-induced cerebral protection against I/R injury. Our findings provide a promising therapeutic approach for treatment of acute cerebral I/R injury.or treatment of acute cerebral I/R injury.)
Xiao 2019 Int J Hypertens + (Although many researches regarding risk fa … Although many researches regarding risk factors for hypertension have been reported, little information is known about the effect of BMI on the prevalence of hypertension considering sex differences. The aim of this study was to examine the sex difference in the prevalence of hypertension with the predicting indicator BMI. A total number of 6330 subjects in Shaanxi were examined using multivariable logistic regression to study the relationship between genders in different levels of BMI and prevalence of hypertension. Overall, females had a higher prevalence of hypertension than males, being 28.36 % and 21.55 %, respectively. The mean of blood pressure and the prevalence of hypertension increased as BMI getting larger. The result of multivariable logistic regression showed that obese and overweight males had higher risk of getting hypertension than their female counterparts. Further prevention of hypertension should be focused on obese and overweight males more than females and examining the mechanism of how sex differences influence the prevalence of hypertension. influence the prevalence of hypertension.)
Hom 2011 Dev Cell + (Although mature myocytes rely on mitochond … Although mature myocytes rely on mitochondria as the primary source of energy, the role of mitochondria in the developing heart is not well known. Here, we find that closure of the mitochondrial permeability transition pore (mPTP) drives maturation of mitochondrial structure and function and myocyte differentiation. Cardiomyocytes at embryonic day (E) 9.5, when compared to E13.5, displayed fragmented mitochondria with few cristae, a less-polarized mitochondrial membrane potential, higher reactive oxygen species (ROS) levels, and an open mPTP. Pharmacologic and genetic closing of the mPTP yielded maturation of mitochondrial structure and function, lowered ROS, and increased myocyte differentiation (measured by counting Z bands). Furthermore, myocyte differentiation was inhibited and enhanced with oxidant and antioxidant treatment, respectively, suggesting that redox-signaling pathways lie downstream of mitochondria to regulate cardiac myocyte differentiation. regulate cardiac myocyte differentiation.)
Gupta 2021 Sci Rep + (Although microRNA-7 (miRNA-7) is known to … Although microRNA-7 (miRNA-7) is known to regulate proliferation of cancer cells by targeting Epidermal growth factor receptor (EGFR/ERBB) family, less is known about its role in cardiac physiology. Transgenic (Tg) mouse with cardiomyocyte-specific overexpression of miRNA-7 was generated to determine its role in cardiac physiology and pathology. Echocardiography on the miRNA-7 Tg mice showed cardiac dilation instead of age-associated physiological cardiac hypertrophy observed in non-Tg control mice. Subjecting miRNA-7 Tg mice to transverse aortic constriction (TAC) resulted in cardiac dilation associated with increased fibrosis bypassing the adaptive cardiac hypertrophic response to TAC. miRNA-7 expression in cardiomyocytes resulted in significant loss of ERBB2 expression with no changes in ERBB1 (EGFR). Cardiac proteomics in the miRNA-7 Tg mice showed significant reduction in mitochondrial membrane structural proteins compared to NTg reflecting role of miRNA-7 beyond the regulation of EGFR/ERRB in mediating cardiac dilation. Consistently, electron microscopy showed that miRNA-7 Tg hearts had disorganized rounded mitochondria that was associated with mitochondrial dysfunction. These findings show that expression of miRNA-7 in the cardiomyocytes results in cardiac dilation instead of adaptive hypertrophic response during aging or to TAC providing insights on yet to be understood role of miRNA-7 in cardiac function.stood role of miRNA-7 in cardiac function.)
Kamunde 2018 Free Radic Biol Med + (Although mitochondria are presumed to emit … Although mitochondria are presumed to emit and consume reactive oxygen species (ROS), the quantitative interplay between the two processes in ROS regulation is not well understood. Here, we probed the role of mitochondrial bioenergetics in H2O2 metabolism using rainbow trout liver and heart mitochondria. Both liver and heart mitochondria emitted H2O2 at rates that depended on their metabolic state, with the emission rates (free radical leak) constituting 0.8-2.9% and 0.2-2.5% of the respiration rate in liver and heart mitochondria, respectively. When presented with exogenous H2O2, liver and heart mitochondria consumed it by first order reactions with half-lives (s) of 117 and 210, and rate constants of 5.96 and 3.37 (× 10-3 s-1), respectively. The mitochondrial bioenergetic status greatly affected the rate of H2O2 consumption in heart but not liver mitochondria. Moreover, the activities and contribution of H2O2 scavenging systems varied between liver and heart mitochondria. The significance of the scavenging systems ranked by the magnitude (%) of inhibition of H2O2 removal after correcting for emission were, liver (un-energized and energized): catalase > glutathione (GSH) ≥ thioredoxin reductase (TrxR); un-energized heart mitochondria: catalase > TrxR > GSH and energized heart mitochondria: GSH > TrxR > catalase. Notably, depletion of GSH evoked a massive surge in H2O2 emission that grossly masked the contribution of this pathway to H2O2 scavenging in heart mitochondria. Irrespective of the organ of their origin, mitochondria behaved as H2O2 regulators that emitted or consumed it depending on the ambient H2O2 concentration, mitochondrial bioenergetic state and activity of the scavenging enzyme systems. Indeed, manipulation of mitochondrial bioenergetics and H2O2 scavenging systems caused mitochondria to switch from being net consumers to net emitters of H2O2. Overall, our data suggest that the low levels of H2O2 typically present in cells would favor emission of this metabolite but the scavenging systems would prevent its accumulation.cavenging systems caused mitochondria to switch from being net consumers to net emitters of H2O2. Overall, our data suggest that the low levels of H2O2 typically present in cells would favor emission of this metabolite but the scavenging systems would prevent its accumulation.)
MacDonald 2018 IOC130 + (Although mitochondria are presumed to emit … Although mitochondria are presumed to emit and consume reactive oxygen species (ROS), the quantitative interplay between the two processes in ROS regulation is not well understood. Here, we probed the role of mitochondrial bioenergetics in H2O2 metabolism using rainbow trout liver and heart mitochondria. Both liver and heart mitochondria emitted H2O2 at rates that depended on their metabolic state, with the emission rates (free radical leak) constituting 0.8 to 2.9% and 0.2 to 2.5% of the respiration rate in liver and heart mitochondria, respectively. When presented with exogenous H2O2, liver and heart mitochondria consumed it by first order reactions with half-lives (s) of 117 and 210, and rate constants of 5.96 and 3.37 (× 10-3 s-1), respectively. The mitochondrial bioenergetic status greatly affected the rate of H2O2 consumption in heart but not liver mitochondria. Moreover, the activities and contribution of H2O2 scavenging systems varied between liver and heart mitochondria. The significance of the scavenging systems ranked by the magnitude (%) of inhibition of H2O2 removal after correcting for emission were, liver (un-energized and energized): catalase > glutathione (GSH) ≥ thioredoxin reductase (TrxR); un-energized heart mitochondria: catalase > TrxR > GSH and energized heart mitochondria: GSH > TrxR > catalase. Notably, depletion of GSH evoked a massive surge in H2O2 emission that grossly masked the contribution of this pathway to H2O2 scavenging in heart mitochondria. Irrespective of the organ of their origin, mitochondria behaved as H2O2 regulators that emitted or consumed it depending on the ambient H2O2 concentration, mitochondrial bioenergetic state and activity of the scavenging enzyme systems. Indeed, manipulation of mitochondrial bioenergetics and H2O2 scavenging systems caused mitochondria to switch from being net consumers to net emitters of H2O2. Overall, our data suggest that the low levels of H2O2 typically present in cells would favor emission of this metabolite but the scavenging systems would prevent its accumulation.cavenging systems caused mitochondria to switch from being net consumers to net emitters of H2O2. Overall, our data suggest that the low levels of H2O2 typically present in cells would favor emission of this metabolite but the scavenging systems would prevent its accumulation.)
Jardim-Messeder 2022 Biochim Biophys Acta Bioenerg + (Although mitochondria have a central role … Although mitochondria have a central role in energy transduction and reactive oxygen species (ROS) production, the regulatory mechanisms and their involvement in plant stress signaling are not fully established. The phytohormone salicylic acid (SA) is an important regulator of mitochondria-mediated ROS production and defense signaling. The role of SA and adenine nucleotides in the regulation of the mitochondrial succinate dehydrogenase (SDH) complex activity and ROS production was analyzed using WT, RNAi SDH1-1 and disrupted stress response 1 (dsr1) mutants, which show a point mutation in SDH1 subunit and are defective in SA signaling. Our results showed that SA and adenine nucleotides regulate SDH complex activity by distinct patterns, contributing to increased SDH-derived ROS production. As previously demonstrated, SA induces the succinate-quinone reductase activity of SDH complex, acting at or near the ubiquinone binding site. On the other hand, here we demonstrated that adenine nucleotides, such as AMP, ADP and ATP, induce the SDH activity provided by the SDH1 subunit. The regulation of SDH activity by adenine nucleotides is dependent on mitochondrial integrity and is prevented by atractyloside, an inhibitor of adenine nucleotide translocator (ANT), suggesting that the regulatory mechanism occurs on the mitochondrial matrix side of the inner mitochondrial membrane, and not in the intermembrane space, as previously suggested. On the other hand, in the intermembrane space, ADP and ATP limit mitochondrial oxygen consumption by a mechanism that appears to be related to cytochrome bc1 complex inhibition. Altogether, these results indicate that SA signaling and adenine nucleotides regulate the mitochondrial electron transport system and mitochondria-derived ROS production by direct effect in the electron transport system complexes, bringing new insights into mechanisms with direct implications in plant development and responses to different environmental responses, serving as a starting point for future physiological explorations.int for future physiological explorations.)
Hervouet 2005 Carcinogenesis + (Although mitochondrial deficiency in cance … Although mitochondrial deficiency in cancer has been described by Warburg, many years ago, the mechanisms underlying this impairment remain essentially unknown. Many types of cancer cells are concerned and, in particular, clear cell renal carcinoma (CCRC). In this cancer, the tumor suppressor gene, VHL (von Hippel-Lindau factor) is invalidated. Previous studies have shown that the transfection of the VHL gene in VHL-deficient cells originating from CCRCs could suppress their ability to form tumors when they were injected into nude mice. However, various additional genetic alterations are observed in such cancer cells. In order to investigate whether VHL invalidation was related to the mitochondrial impairment, we have studied the effects of wild-type VHL transfection into VHL-deficient 786-0 or RCC10 cells on their oxidative phosphorylation (OXPHOS) subunit contents and functions. We show that the presence of wild-type VHL protein (pVHL) increased mitochondrial DNA and respiratory chain protein contents and permitted the cells to rely on their mitochondrial ATP production to grow in the absence of glucose. In parallel to mtDNA increase, the presence of pVHL up regulated the mitochondrial transcription factor A, as shown by western blot analysis. In conclusion, in CCRCs, pVHL deficiency is one of the factors responsible for down-regulation of the biogenesis of OXPHOS complexes.ion of the biogenesis of OXPHOS complexes.)
Kukat 2014 PLoS Genet + (Although mitochondrial dysfunction is ofte … Although mitochondrial dysfunction is often accompanied by excessive reactive oxygen species (ROS) production, we previously showed that an increase in random somatic mtDNA mutations does not result in increased oxidative stress. Normal levels of ROS and oxidative stress could also be a result of an active compensatory mechanism such as a mild increase in proton leak. Uncoupling protein 2 (UCP2) was proposed to play such a role in many physiological situations. However, we show that upregulation of UCP2 in mtDNA mutator mice is not associated with altered proton leak kinetics or ROS production, challenging the current view on the role of UCP2 in energy metabolism. Instead, our results argue that high UCP2 levels allow better utilization of fatty acid oxidation resulting in a beneficial effect on mitochondrial function in heart, postponing systemic lactic acidosis and resulting in longer lifespan in these mice. This study proposes a novel mechanism for an adaptive response to mitochondrial cardiomyopathy that links changes in metabolism to amelioration of respiratory chain deficiency and longer lifespan.tory chain deficiency and longer lifespan.)
Karamercan 2013 Shock + (Although mitochondrial dysfunction is thou … Although mitochondrial dysfunction is thought to contribute to the development of posttraumatic organ failure, current techniques to assess mitochondrial function in tissues are invasive and clinically impractical. We hypothesized that mitochondrial function in peripheral blood mononuclear cells (PBMCs) would reflect cellular respiration in other organs during hemorrhagic shock and resuscitation.Using a fixed-pressure HS model, Long-Evans rats were bled to a mean arterial pressure of 40 mmHg. When blood pressure could no longer be sustained without intermittent fluid infusion (decompensated HS), lactated Ringer's solution was incrementally infused to maintain the mean arterial pressure at 40 mmHg until 40% of the shed blood volume was returned (severe HS). Animals were then resuscitated with 4× total shed volume in lactated Ringer's solution over 60 min (resuscitation). Control animals underwent the same surgical procedures, but were not hemorrhaged. Animals were randomized to control (''n'' = 6), decompensated HS (''n'' = 6), severe HS (''n'' = 6), or resuscitation (''n'' = 6) groups. Kidney, liver, and heart tissues as well as PBMCs were harvested from animals in each group to measure mitochondrial oxygen consumption using high-resolution respirometry. Flow cytometry was used to assess mitochondrial membrane potential (Ψm) in PBMCs. One-way analysis of variance and Pearson correlations were performed.Mitochondrial oxygen consumption decreased in all tissues, including PBMCs, following decompensated HS, severe HS, and resuscitation. However, the degree of impairment varied significantly across tissues during hemorrhagic shock and resuscitation. Of the tissues investigated, PBMC mitochondrial oxygen consumption and Ψm provided the closest correlation to kidney mitochondrial function during HS (complex I: ''r'' = 0.65; complex II: ''r'' = 0.65; complex IV: ''r'' = 0.52; ''P'' < 0.05). This association, however, disappeared with resuscitation. A weaker association between PBMC and heart mitochondrial function was observed, but no association was noted between PBMC and liver mitochondrial function.All tissues including PBMCs demonstrated significant mitochondrial dysfunction following hemorrhagic shock and resuscitation. Although PBMC and kidney mitochondrial function correlated well during hemorrhagic shock, the variability in mitochondrial response across tissues over the spectrum of hemorrhagic shock and resuscitation limits the usefulness of using PBMCs as a proxy for tissue-specific cellular respiration.oxy for tissue-specific cellular respiration.)
Wang 2011 Mol Oncol + (Although mitochondrial respiration is decr … Although mitochondrial respiration is decreased in most cancer cells, the role of this decrease in carcinogenesis and cancer progression is still unclear. To better understand this phenomenon, instead of further inhibiting mitochondrial function, we induced mitochondrial biogenesis in transformed cells by activating the peroxisome proliferator-activated receptors (PPARs)/peroxisome proliferator-activated receptor gamma co-activator 1α [[PGC-1alpha|(PGC-1α)]] pathways. This was achieved by treating the cells with bezafibrate, a PPARs panagonist that also enhances [[PGC-1α]] expression. We confirmed that bezafibrate treatment led to increased mitochondrial proteins and enzyme functions. We found that cells with increased mitochondrial biogenesis had decreased growth rates in glucose-containing medium. In addition, they became less invasive, which was directly linked to the reduced lactate levels. Surprisingly, even though bezafibrate-treated cells had higher levels of mitochondrial markers, total respiration was not significantly altered. However, respiratory coupling, and ATP levels were. Our data show that by increasing the efficiency of the mitochondrial oxidative phosphorylation system, cancer progression is hampered by decreases in cell proliferation and invasiveness.es in cell proliferation and invasiveness.)
Hickey 2009 Am J Physiol Cell Physiol + (Although most attention has been focused o … Although most attention has been focused on mitochondrial ATP production and transfer in failing hearts, less has been focused on the nonfailing hypertensive heart. Here, energetic complications are less obvious, yet they may provide insight into disease ontogeny. We studied hearts from 12-mo-old spontaneously hypertensive rats (SHR) relative to normotensive Wistar-Kyoto (WKY) rats. The ex vivo working-heart model of SHR showed reduced compliance and impaired responses to increasing preloads. High-resolution respirometry showed higher state 3 (with excess ADP) respiration in SHR left ventricle fibers with complex I substrates and maximal uncoupled respiration with complex I + complex II substrates. Respiration with ATP was depressed 15% in SHR fibers relative to WKY fibers, suggesting impaired ATP hydrolysis. This finding was consistent with a 50% depression of actomyosin ATPase activities. Superoxide production from SHR fibers was similar to that from WKY fibers respiring with ADP; however, it was increased by 15% with ATP. In addition, the apparent ''K''m for ADP was 54% higher for SHR fibers, and assays conducted after ''ex vivo'' work showed a 28% depression of complex I in SHR, but not WKY, fibers. Transmission electron microscopy showed similar mitochondrial volumes but a decrease in the number of cristae in SHR mitochondria. Tissue lipid peroxidation was also 15% greater in SHR left ventricle. Overall, these data suggest that although cardiac mitochondria from nonfailing SHR hearts function marginally better than those from WKY hearts, they show dysfunction after intense work. Impaired ATP turnover in hard-working SHR hearts may starve cardiac mitochondria of ADP and elevate superoxide.ve cardiac mitochondria of ADP and elevate superoxide.)
Dejean 2001 Biochim Biophys Acta + (Although on-line calorimetry has been wide … Although on-line calorimetry has been widely used to detect transitions in global metabolic activity during the growth of microorganisms, the relationships between oxygen consumption flux and heat production are poorly documented. In this work, we developed a respirometric and calorimetric approach to determine the enthalpy efficiency of respiration-linked energy transformation of isolated yeast mitochondria and yeast cells under growing and resting conditions. On isolated mitochondria, the analysis of different phosphorylating and non-phosphorylating steady states clearly showed that the simultaneous measurements of heat production and oxygen consumption rates can lead to the determination of both the enthalpy efficiency and the ATP/O yield of oxidative phosphorylation. However, these determinations were made possible only when the net enthalpy change associated with the phosphorylating system was different from zero. On whole yeast cells, it is shown that the simultaneous steady state measurements of the heat production and oxygen consumption rates allow the enthalpy growth efficiency (i.e. the amount of energy conserved as biomass compared to the energy utilised for complete catabolism plus anabolism) to be assessed. This method is based on the comparison between the calorimetric-respirometric ratio (CR ratio) determined under growth versus resting conditions during a purely aerobic metabolism. Therefore, in contrast to the enthalpy balance approach, this method does not rely on the exhaustive and tedious determinations of the metabolites and elemental composition of biomass. Thus, experiments can be performed in the presence of non-limiting amounts of carbon substrate, an approach which has been successfully applied to slow growing cells such as yeast cells expressing wild-type or a mutant rat uncoupling protein-1.type or a mutant rat uncoupling protein-1.)
Ali 2014 Abstract MiP2014 + (Although originally defined as harmful byp … Although originally defined as harmful byproducts of aerobic metabolism, reactive oxygen species (ROS) are currently believed to play a critical role in downstream signaling, which regulates protein kinases, phosphatases, transcription factors and ion transport channels. However, mechanisms by which ROS is responsively produced, sensed and translated in cellular domains, especially neurons, remain elusive. Recently, NADPH oxidase (NOX), which is a multimeric enzyme that catalyzes the production of superoxide (O2•) from O2 and NADPH and was originally identified in neutrophils as essential for the host response respiratory burst, has been shown to localize in the brain. The unexpected presence of NOX in neurons has led to the idea that NOX-induced ROS are important in non-host defense contexts; e.g. intracellular and intercellular redox signaling. In previous works, we showed that NOX is actively producing O2• in the brain and might therefore be an important element that influences redox homeostasis in health, disease, and aging. Questions on specific connections between NOX activation and neuronal dysfunctions remain open for exploration by unconventional experimental approaches capable of probing the implications of in vivo NOX assembly and activation. Here, we studied oxygen-consuming, superoxide-producing NOX basal as well as induced activities in synaptosomes. Isolated synaptosomes (severed nerve terminals) are studied because they contain all necessary components of a functional neuronal environment including ion channels, receptors, and mitochondria. We demonstrate the ability of the Oroboros Oxygraph-2k, in parallel with spin-trapping/labeling electron paramagnetic resonance (EPR) techniques, to study sources and dynamics of ROS in synaptosomes. To the best of our knowledge, this is the first time that the Oroboros system has been employed to quantify NOX activity in synaptosomes. to quantify NOX activity in synaptosomes.)
Maddalena 2017 Biochem Biophys Res Commun + (Although oxygen levels in the extracellula … Although oxygen levels in the extracellular space of most mammalian tissues are just a few percent, under standard cell culture conditions they are not regulated and are often substantially higher. Some cellular sources of reactive oxygen species, like NADPH oxidase 4, are sensitive to oxygen levels in the range between 'normal' physiological (typically 1-5%) and standard cell culture (up to 18%). Hydrogen peroxide in particular participates in signal transduction pathways via protein redox modifications, so the potential increase in its production under standard cell culture conditions is important to understand. We measured the rates of cellular hydrogen peroxide production in some common cell lines, including C2C12, PC-3, HeLa, SH-SY5Y, MCF-7, and mouse embryonic fibroblasts (MEFs) maintained at 18% or 5% oxygen. In all instances the rate of hydrogen peroxide production by these cells was significantly greater at 18% oxygen than at 5%. The increase in hydrogen peroxide production at higher oxygen levels was either abolished or substantially reduced by treatment with GKT 137831, a selective inhibitor of NADPH oxidase subunits 1 and 4. These data indicate that oxygen levels experienced by cells in culture influence hydrogen peroxide production via NADPH oxidase 1/4, highlighting the importance of regulating oxygen levels in culture near physiological values. However, we measured pericellular oxygen levels adjacent to cell monolayers under a variety of conditions and with different cell lines and found that, particularly when growing at 5% incubator oxygen levels, pericellular oxygen was often lower and variable. Together, these observations indicate the importance, and difficulty, of regulating oxygen levels experienced by cells in culture.en levels experienced by cells in culture.)
Ponce 2019 Thesis + (Although pathological alterations in gene … Although pathological alterations in gene expression and mitochondria function in response to cardiac ischemia are well recognized, the mechanisms driving these changes are incompletely understood. Nuclear to mitochondrial communication regulating gene expression and mitochondrial function is a critical process following cardiac ischemic injury. Here we determine that cyclin C, a component of the transcriptional regulator, Mediator complex, directly regulates cardiac and mitochondrial function by modifying mitochondrial fission. We tested the hypothesis that cyclin C has a binary function as a transcriptional cofactor in the nucleus and acute regulation of cardiac energetics in ischemia by enhancing mitochondrial fission in the cytoplasm.In response to stress, cyclin C translocates to the cytoplasm enhancing mitochondria fission in part through interactions with Cdk1. Using cardiac specific cyclin C knockout and overexpression mouse models, we determined cyclin C regulates mitochondria morphology under basal and ischemic conditions ''in vivo''. Furthermore, pretreatment with a Cdk1 inhibitor followed by ischemia ''in vivo'' results in reduced mitochondrial fission. Together, our study reveals that cyclin C regulates both hypertrophic gene expression and mitochondrial fission providing new insights into the regulation of cardiac energy metabolism following acute ischemic injury.etabolism following acute ischemic injury.)
Chang 2016 Transl Res + (Although restoration of mitochondrial func … Although restoration of mitochondrial function in mitochondrial diseases through peptide-mediated allogeneic mitochondrial delivery (PMD) has been demonstrated ''in vitro'', the ''in vivo'' therapeutic efficacy of PMD in Parkinson's disease (PD) has yet to be determined. In this study, we compared the functionality of mitochondrial transfer with or without Pep-1 conjugation in neurotoxin (6-hydroxydopamine, 6-OHDA)-induced PC12 cells and PD rat models. We injected mitochondria into the medial forebrain bundle (MFB) of the PD rats after subjecting the nigrostriatal pathway to a unilateral 6-OHDA lesion for 21 days, and we verified the effectiveness of the mitochondrial graft in enhancing mitochondrial function in the soma of the substantia nigra (SN) neuron through mitochondrial transport dynamics in the nigrostriatal circuit. The result demonstrated that only PMD with allogeneic and xenogeneic sources significantly sustained mitochondrial function to resist the neurotoxin-induced oxidative stress and apoptotic death in the rat PC12 cells. The remaining cells exhibited a greater capability of neurite outgrowth. Furthermore, allogeneic and xenogeneic transplantation of peptide-labeled mitochondria after 3 months improved the locomotive activity in the PD rats. This increase was accompanied by a marked decrease in dopaminergic neuron loss in the substantia nigra pars compacta (SNc) and consistent enhancement of tyrosine hydroxylase-positive immunoreaction of dopaminergic neurons in the SNc and striatum. We also observed that in the SN dopaminergic neuron in the treated PD rats, mitochondrial complex I protein and mitochondrial dynamics were restored, thus ameliorating the oxidative DNA damage. Moreover, we determined signal translocation of graft allogeneic mitochondria from the MFB to the calbindin-positive SN neuron, which demonstrated the regulatory role of mitochondrial transport in alleviating 6-OHDA-induced degeneration of dopaminergic neurons.Copyright © 2016 Elsevier Inc. All rights reserved. © 2016 Elsevier Inc. All rights reserved.)
McFarlane 2017 Am J Physiol Regul Integr Comp Physiol + (Although seasonal modifications of brown a … Although seasonal modifications of brown adipose tissue (BAT) in hibernators are well documented, we know little about functional regulation of BAT in different phases of hibernation. In the 13-lined ground squirrel, liver mitochondrial respiration is suppressed by up to 70% during torpor. This suppression is reversed during arousal and interbout euthermia (IBE), and corresponds with patterns of maximal activities of electron transport system (ET-pathway) enzymes. Uncoupling of BAT mitochondria is controlled by free fatty acid release stimulated by sympathetic activation of adipocytes, so we hypothesized that further regulation at the level of the ET-pathway would be of little advantage. As predicted, maximal ET-pathway enzyme activities of isolated BAT mitochondria did not differ between torpor and IBE. In contrast to this pattern, respiration rates of mitochondria isolated from torpid individuals were suppressed by ~60% compared with rates from IBE individuals when measured at 37°C. At 10°C, however, mitochondrial respiration rates tended to be greater in torpor than IBE. As a result, the temperature sensitivity (Q10) of mitochondrial respiration was significantly lower in torpor (~1.4) than IBE (~2.4), perhaps facilitating energy savings during entrance into torpor and thermogenesis at low body temperatures. Despite the observed differences in isolated mitochondria, norepinephrine-stimulated respiration rates of isolated BAT adipocytes did not differ between torpor and IBE, perhaps because the adipocyte isolation requires lengthy incubation at 37°C, potentially reversing any changes that occur in torpor. Such changes may include remodeling of BAT mitochondrial membrane phospholipids, which could change ''in situ'' enzyme activities and temperature sensitivities.Copyright © 2017 the American Physiological Society.© 2017 the American Physiological Society.)
Menze 2013 Abstract MiP2013 + (Although severe water loss is often detrim … Although severe water loss is often detrimental to life, some exceptional animals have developed mechanisms to survive water loss to 0.02–0.05 g H2O/g dry mass (anhydrobiosis). How the structural and functional integrity of the mitochondrion is maintained during desiccation and rehydration is currently not understood. The brine shrimp Artemia franciscana serves as an important model organism for anhydrobiosis. Desiccation tolerance in this animal is correlated with the accumulation of large amounts of highly hydrophilic macromolecules termed Late Embryogenesis Abundant (LEA) proteins. Most LEA proteins are intrinsically disordered in solution and thought to stabilize other proteins and membranes during desiccation [1]. Two mitochondrial targeted LEA proteins, AfrLEA3m and AfLEA1.3, have been described in A. franciscana and may help to maintain the integrity and functionality of the organelle when water is scarce [2, 3]. In order to evaluate the impact of AfLEA1.3 on water-stress tolerance of mitochondria the protein was transgenically expressed in Kc167 cells from the desiccation intolerant fruit fly Drosophila melanogaster [4]. A protein construct composed of AfLEA1.3 and green fluorescent protein was found to accumulate within mitochondria. Expression of AfLEA1.3 in non-permeabilized cells reduced mitochondrial proton leak by 20-30% in presence and absence of hyperosmotic stress. Oxygen consumption of permeabilized cells in presence of mixed substrates and ADP was 18% less inhibited by increasing concentrations of NaCl in cells expressing AfLEA1.3 compared to control cells. Mitochondria isolated from wild-type and AfLEA1.3 expressing cells showed a high respiratory control ratio (RCR) of 11.3 ± 1.4. Oxygen consumption in presence of ADP and substrates that supply NADH to Complex I were significantly reduced after freezing and thawing and this reduction was significantly greater in mitochondria from control cells (RCR = 7.3 ± 1.0) than in cells expressing AfLEA1.3 (RCR = 10.1 ± 0.7, ''P''< 0.05). Expression of AfLEA1.3 improved functions of mitochondria from D. melanogaster in several models of water stress. Protection was observed at hydration states in which AfLEA1.3 most likely lacks extensive secondary structure and the protein was most likely intrinsically disordered. AfLEA1.3 thus can operate outside the classic structure function paradigm. However, the observed effects afforded by the hydrated AfLEA1.3 protein do not preclude even greater stabilization of biological structure and function in the dried state.al structure and function in the dried state.)
Stickle 1989 Biol Bull + (Although some species of fish, crustaceans … Although some species of fish, crustaceans, and molluscs may behaviorally avoid hypoxic masses of small size and limited duration, others cannot. In a series of crustaceans, tolerance of hypoxia over 28 days at 30 °C, decreases as follows: ''Eurypanopeus depressus'' (38 Torr = LC50) > ''Palaemonetes pugio'' > ''Rhithropanopeus harrisii'' > ''Penaeus aztecus'' > ''Callinectes sapidus' (121 Torr = LC50). ''Callinectes sapidus'' and ''E. depressus'' die during 12-h exposure to anoxia and their heat dissipation rates (quantified by microcalorimetry) are depressed in seawater at 25 % air saturation (normoxia) to only 32 and 47 % of their metabolic rate at normoxia. In contrast, starved ''Crassostrea virginica'' and ''Thais haemastoma'' are anoxia tolerant; their metabolic rates are depressed under anoxia to 75 % and 9 % of the normoxic rate. Hypoxia tolerance is greater at 20 °C than at 30 °C for ''Penaeus aztecus'' and ''Crassostrea virginica'', but no temperature effect on tolerance exists for ''Callinectes sapidus''. Hypoxia tolerance varies inversely with salinity for Penaeus aztecus at 20 ° and 30 °C and for ''Callinectes sapidus'' at 30 °C, but it varies directly with salinity at 20 °C in ''Callinectes sapidus''. Greater depression of metabolic rate occurs in molluscs during anoxia exposure (and is correlated with greater hypoxia tolerance) than occurs in ''Callinectes sapidus'' and ''Penaeus aztecus'', which are not anoxia tolerant. Heavy mortality probably occurs in young ''Callinectes sapidus'' and ''Penaeus aztecus'' and in stages of the life history when the organisms are incapable of avoiding hypoxic water masses.anisms are incapable of avoiding hypoxic water masses.)
Rhee 1999 Exp Mol Med + (Although superoxide anions (O2.-) and H2O2 … Although superoxide anions (O2.-) and H2O2 are generally considered to be toxic by-products of respiration, recent evidence suggests that the production of these reactive oxygen species (ROS) might be an integral component of membrane receptor signaling. In mammalian cells, a variety of extracellular stimuli have recently been shown to induce a transient increase in the intracellular concentration of ROS, and specific inhibition of the ROS generation resulted in a complete blockage of stimulant-dependent signaling. In the next few years, therefore, a flurry of research activity is expected in relation to the elucidation of ROS production in response to receptor stimulation, identification of ROS target molecules, and investigation of ROS elimination. The goal of this report is to review our current knowledge of ROS-regulated signal transduction and propose future directions.ransduction and propose future directions.)
Hawkins 1985 Mar Ecol Prog Ser + (Although sustained predominantly by nutrie … Although sustained predominantly by nutrients obtained directly from the environment, metabolic requirements for both gametogenesis and general maintenance in an open-shore population of the bivalve mollusc ''Mytilus edulis'' L. from southwest England were also 'subsidized' from substantial energy reserves accumulated during periods of somatic growth. Depletion of these reserves over late winter was associated with a greater sensitivity in the rate of oxidative metabolism to exogenous nutrient availability, diminished metabolic efficiencies with which absorbed ration was utilized, and an associated increase in the instantaneous maintenance requirements. Absorption rates, which were nevertheless minimal during winter, are suggested to be endogenously regulated in a manner more indicative of time-averaged than immediate optimization. It is proposed that such regulation may be especially adaptive within ''M. edulis'', a sedentary species that experiences pronounced annual cycles of food availability, and in which costs deriving from feeding and associated activities are shown to add as much as 38 % to standard metabolic demands.uch as 38 % to standard metabolic demands.)
Gray 1998 Nucleic Acids Res + (Although the collection of completely sequ … Although the collection of completely sequenced mitochondrial genomes is expanding rapidly, only recently has a phylogenetically broad representation of mtDNA sequences from protists (mostly unicellular eukaryotes) become available. This review surveys the 23 complete protist mtDNA sequences that have been determined to date, commenting on such aspects as mitochondrial genome structure, gene content, ribosomal RNA, introns, transfer RNAs and the genetic code and phylogenetic implications. We also illustrate the utility of a comparative genomics approach to gene identification by providing evidence that orfB in plant and protist mtDNAs is the homolog of atp8 , the gene in animal and fungal mtDNA that encodes subunit 8 of the F0portion of mitochondrial ATP synthase. Although several protist mtDNAs, like those of animals and most fungi, are seen to be highly derived, others appear to be have retained a number of features of the ancestral, proto-mitochondrial genome. Some of these ancestral features are also shared with plant mtDNA, although the latter have evidently expanded considerably in size, if not in gene content, in the course of evolution. Comparative analysis of protist mtDNAs is providing a new perspective on mtDNA evolution: how the original mitochondrial genome was organized, what genes it contained, and in what ways it must have changed in different eukaryotic phyla.ave changed in different eukaryotic phyla.)

(Although the collection of completely sequenced mitochondrial genomes is)

Agrimi 2014 Abstract IOC 2014-04 Schroecken + (Although the decrease of pyruvate secretio … Although the decrease of pyruvate secretion by brewer’s yeasts during fermentation has long been desired in the alcohol beverage industry, rather little is known about the regulation of pyruvate accumulation. In this study, we have characterized a previously developed a pyruvate undersecreting sake yeast obtained by isolating a strain (TCR7) tolerant to ethyl α-transcyanocinnamate, an inhibitor of pyruvate transport into mitochondria. To obtain insights into pyruvate metabolism, we investigated the mitochondrial activity of TCR7 by oxigraphy and 13C-metabolic flux analysis during aerobic growth . While mitochondrial pyruvate oxidation was higher, glycerol production was decreased in TCR7 compared to the reference. These results indicate that mitochondrial activity is elevated in the TCR7 strain with the consequence of decreased pyruvate accumulation. Surprisingly mitochondrial activity is much higher in the sake yeast compared to CEN.PK 113-7D, the reference strain in metabolic engineering. When shifted from aerobic to anaerobic conditions, sake yeast retains a branched mitochondrial structure for a longer time than laboratory strains. The regulation of mitochondrial activity can become a completely novel approach to manipulate metabolic profile during fermentation of brewer’s yeasts.[[File:Abstract Agrimi G Graphical.jpg|center|450px]]e:Abstract Agrimi G Graphical.jpg|center|450px]])
Pardee 1948 J Biol Chem + (Although the inhibition of succinic dehydr … Although the inhibition of succinic dehydrogenase by oxalacetate is a generally accepted fact, there is a paucity of data on the subject. In 1937Das (l), using a modified Thunberg technique, reported that the enzyme was 50 per cent inhibited by 2 X 1O-5 M oxalacetate when the succinateconcentration was 0.025 M. In 1939 Potter (2) reported that the oxidation of succinate by liver and kidney homogenates was inhibited bycozymase (DPN). Keilin and Hartree (3) and Mann and Quastel (4) attributed this effect, no doubt correctly, to the formation of oxalacetate,although no data on the effect of oxalacetate were presented. The inhibitory effect of DPN upon the succinate system was later studied bySwingle, Axelrod, and Elvehjem (5) who also determined the effect of oxalacetate upon the succinic dehydrogenase system by measuring oxygenuptake. They reported that at succinate concentrations of 0.045 M oxalacetate produced 98, 65, and 22 per cent inhibition at concentrations of50, 10, and 5 X 10e5 M. From the data given it is not possible to tell whether the inhibition was transitory, as will be shown below, or whetherthe experiments were of such short duration that the decreased inhibition was not revealed. Since we found that the inhibition declined with time,it is clear that the earlier experiments (1,5) cannot be accepted as quantitative measures of the inhibition by oxalacetate. They do, however, establish the fact that this substance has a remarkable affinity for the succinic enzyme; remarkable because it appears to be at least 1000 times greater than the affinity of the normal substrate for the enzyme, and because oxalacetate has been assumed to be formed in the course of succinate oxidation. If the physiologically formed oxalacetate were as toxic to succinate oxidation as added oxalacetate, the inhibition would have profound regulatory effects upon oxidative metabolism. Such does not seem to be the case, however, although the reasons are as yet obscure....hough the reasons are as yet obscure. ...)
Tartaro 2015 Transplant Proc + (Although the intermittent Pringle maneuver … Although the intermittent Pringle maneuver is used for major transplant surgery, traumas, and hepatic protection, long ischemia time and reperfusion may limit some protection in Wistar rats. The aim of the study was to evaluate the protection effects of intermittent clamping in the total hepatic pedicle after a long period of ischemia and reperfusion in Wistar rats.Forty-two male Wistar rats, weighing ± 327.7 g, were anesthetized intravenously with sodium thiopental and given a U-shaped incision in the abdomen. The total hepatic pedicle was isolated and subjected to clamping with a microvascular clamp. Groups included were the continuous group (CG, n = 14, 40 minutes of ischemia/40 minutes of reperfusion); the intermittent group (IG, n = 14, 4 cycles a 10 minute ischemia/reperfusion 10 minutes); and the sham group (SG, n = 14, 80 minutes of observation time). Blood collection for transaminase dosage was carried out, and hepatic biopsy specimens were taken for mitochondrial respiration and histological evaluation.In groups CG and IG, aspartate aminotransferase and alanine aminotransferase enzymes were elevated in comparison to group SG (P < .008); mitochondrias, when stimulated by use of adenosine diphosphate or carbonylcyanide p-trifluoromethoxyphenylhydrazone, had a significant decrease in mitochondrial respiration (P < .05), and the respiratory control ratio in the ischemic groups was lower (P < .03) when compared with the GS. On histological examination, 100% of the GC had lesions: 33% focal hemorrhagic necrosis, 17% sinuzoidal congestion and/or vacuolization, and 50% venous congestion; in the IG, 100% had lesions: 43% sinusoidal congestion and/or vacuolization and 57% venous congestion.The intermittent total hepatic pedicle clamping for a long period of time in the Wistar rats had no efficacy in protection of liver injury.Copyright © 2015 Elsevier Inc. All rights reserved.pyright © 2015 Elsevier Inc. All rights reserved.)
Ocloo 2017 J Appl Pharmac Sc + (Although the molluscicidal activity of cru … Although the molluscicidal activity of crude dichloromethane extract of ''Millettia thonningii'', known to be rich in alpinumisoflavones was attributed to its inhibition of isolated rat liver mitochondrial complex I activity, the effects of the constituent alpinuisoflavones on mitochondrial function have not been reported. The present study, therefore investigated the effect of O, O-dimethyl-alpinumisoflavone, a constituent of the crude dichloromethane extract of ''M. thonningii'' seeds and 4'-O-methyl-alpinumsioflavone, a naturally occurring alpinumisoflavone in ''Lonchocarpus glabrescens'' in isolated rat liver mitochondria and permeabilised mouse heart fibers using substrate-inhibitor titrations. The O, O-dimethyl-alpinumisoflavone inhibited State 3 respirations supported by glutamate/malate (complex I), succinate (complex II) and Ascorbate/TMPD (complex IV) in the permeabilised cardiac tissues but inhibited only the State 3 respiration supported by glutamate (complex I) in the isolated rat liver mitochondria. The 4'-O-methyl-alpinumsioflavone on the other hand inhibited State 3 respirations supported by all the substrates in both the isolated rat liver mitochondria and the permeabilised cardiac tissues. Thus, whilst O, O-dimethyl-alpinumisoflavone, a naturally occurring phyto-compound in the extract of ''M. thonningii'' seeds inhibits mitochondrial respiratory chain activity essentially at complex I, its derivative 4'-O-methyl-alpinumisoflavone, a naturally occurring phytocompound in ''Lonchocarpus glabrescens'' inhibits mitochondrial respiratory complexes I, II and IV.ndrial respiratory complexes I, II and IV.)
Tesori 2015 Sci Rep + (Although the only effective drug against p … Although the only effective drug against primary hepatocarcinoma, the multikinase inhibitor Sorafenib (SFB) usually fails to eradicate liver cancer. Since SFB targets mitochondria, cell metabolic reprogramming may underlie intrinsic tumor resistance. To characterize cancer cell metabolic response to SFB, we measured oxygen consumption, generation of reactive oxygen species (ROS) and ATP content in rat LCSC (Liver Cancer Stem Cells) -2 cells exposed to the drug. Genome wide analysis of gene expression was performed by Affymetrix technology. SFB cytotoxicity was evaluated by multiple assays in the presence or absence of metabolic inhibitors, or in cells genetically depleted of mitochondria. We found that low concentrations (2.5-5 μM) of SFB had a relatively modest effect on LCSC-2 or 293 T cell growth, but damaged mitochondria and increased intracellular ROS. Gene expression profiling of SFB-treated cells was consistent with a shift toward aerobic glycolysis and, accordingly, SFB cytotoxicity was dramatically increased by glucose withdrawal or the glycolytic inhibitor 2-DG. Under metabolic stress, activation of the AMP dependent Protein Kinase (AMPK), but not ROS blockade, protected cells from death. We conclude that mitochondrial damage and ROS drive cell killing by SFB, while glycolytic cell reprogramming may represent a resistance strategy potentially targetable by combination therapies.ially targetable by combination therapies.)
Tapia 2015 Crit Care + (Although the prognostic value of persisten … Although the prognostic value of persistent hyperlactatemia in septic shock is unequivocal, its physiological determinants are controversial. Particularly, the role of impaired hepatic clearance has been underestimated and is only considered relevant in patients with liver ischemia or cirrhosis. Our objectives were to establish whether endotoxemia impairs whole body net lactate clearance, and to explore a potential role for total liver hypoperfusion during the early phase of septic shock.After anesthesia, 12 sheep were subjected to hemodynamic/perfusion monitoring including hepatic and portal catheterization, and a hepatic ultrasound flow probe. After stabilization (point A), sheep were alternatively assigned to lipopolysaccharide (LPS) (5 mcg/kg bolus followed by 4 mcg/kg/h) or sham for a three-hour study period. After 60 minutes of shock, animals were fluid resuscitated to normalize mean arterial pressure. Repeated series of measurements were performed immediately after fluid resuscitation (point B), and one (point C) and two hours later (point D). Monitoring included systemic and regional hemodynamics, blood gases and lactate measurements, and ''ex-vivo'' hepatic mitochondrial respiration at point D. Parallel exogenous lactate and sorbitol clearances were performed at points B and D. Both groups included an intravenous bolus followed by serial blood sampling to draw a curve using the least squares method.Significant hyperlactatemia was already present in LPS as compared to sham animals at point B (4.7 (3.1 to 6.7) versus 1.8 (1.5 to 3.7) mmol/L), increasing to 10.2 (7.8 to 12.3) mmol/L at point D. A significant increase in portal and hepatic lactate levels in LPS animals was also observed. No within-group difference in hepatic DO2, VO2 or O2 extraction, total hepatic blood flow (point D: 915 (773 to 1,046) versus 655 (593 to 1,175) ml/min), mitochondrial respiration, liver enzymes or sorbitol clearance was found. However, there was a highly significant decrease in lactate clearance in LPS animals (point B: 46 (30 to 180) versus 1,212 (743 to 2,116) ml/min, P <0.01; point D: 113 (65 to 322) versus 944 (363 to 1,235) ml/min, P <0.01).Endotoxemia induces an early and severe impairment in lactate clearance that is not related to total liver hypoperfusion.re impairment in lactate clearance that is not related to total liver hypoperfusion.)
Boveris 1999 Methods Enzymol + (Although the regulation of mitochondrial r … Although the regulation of mitochondrial respiration and energy production in mammalian tissues has been exhaustively studied and extensively reviewed, a clear understanding of the regulation of cellular respiration has not yet been achieved. In particular, the role of tissue pO2 as a factor regulatingcellular respiration remains controversial. The concept of a complex and multisite regulation of cellular respiration and energy production signaled bycellular and intercellular messengers has evolved in the last few years and isstill being researched. A recent concept that regulation of cellular respirationis regulated by ADP, O2 and NO preserves the notion that energy demandsdrive respiration but places the kinetic control of both respiration and energysupply in the availability of ADP to F1-ATPase and of O2 and NO to cytochromeoxidase. In addition, recent research indicates that NO participates inredox reactions in the mitochondrial matrix that regulate the intramitochondrialsteady state concentration of NO itself and other reactive species such assuperoxide radical (O2−) and peroxynitrite (ONOO−). In this way, NO acquiresan essential role as a mitochondrial regulatory metabolite. NO exhibits a richbiochemistry and a high reactivity and plays an important role as intercellularmessenger in diverse physiological processes, such as regulation of blood flow,neurotransmission, platelet aggregation and immune cytotoxic response.aggregation and immune cytotoxic response.)
Meszaros 2014 Abstract MiP2014 + (Although the renaissance of functional mit … Although the renaissance of functional mitochondrial studies targets many tissues and organs, small intestinal mitochondria are less frequently examined. Nevertheless, the integrity of small intestinal mucosa is potentially threatened in various local and systemic pathologies, such as ischemia-reperfusion, septic shock or inflammatory bowel diseases. Mitochondrial dysfunction is critically involved in the pathomechanism of these diseases. Furthermore, timely restitution of adequate mitochondrial function can be a key step towards potentially effective therapeutic strategies.Our goal was to provide firm experimental data for functional mitochondrial investigations, and as a first step, we aimed to test and validate the available methods used for isolation of small intestinal mitochondria in rodents [1,2]. Whole thickness small intestinal mucosal samples of rats and guinea pigs were used, and mitochondria were isolated according to published protocols using chelating agents and differential centrifugation. The assessment of the functional state of isolated mitochondria was performed by means of high-resolution respirometry (Oroboros Oxygraph-2k). The integrity of the outer mt-membrane was tested with cytochrome ''c'' addition and photometric assay for mitochondrial swelling, while membrane potential changes were monitored by safranin fluorescence measurements.In case of rat samples, low respiratory control rates and extremely high cytochrome ''c'' responses were found, and swelling of mitochondria indicated serious damage of the outer mt-membrane. In contrast, guinea pig mitochondria were presented with good respiratory control, low cytochrome ''c'' response and baseline swelling parameters.Based on high-resolution respirometry we conclude that using the accessible, published methodologies, only functionally impaired mitochondria can be isolated from the rat. However, high quantities of intact and well coupled mitochondria can be obtained from the guinea pig. These mitochondria are suitable for further focused studies. Further methodological investigations, possible modifications or even new protocols are needed in order to clarify the cause of this significant interspecies difference. this significant interspecies difference.)
Paumelle 2019 J Hepatol + (Although the role of inflammation to comba … Although the role of inflammation to combat infection is known, the contribution of metabolic changes in response to sepsis is poorly understood. Sepsis induces the release of lipid mediators, many of which activate nuclear receptors such as the peroxisome proliferator-activated receptor (PPAR)α, which controls both lipid metabolism and inflammation. However, the role of hepatic PPARα in the response to sepsis is unknown.Sepsis was induced by intraperitoneal injection of Escherichia coli in different models of cell-specific Pparα-deficiency and their controls. The systemic and hepatic metabolic response was analysed using biochemical, transcriptomic and functional assays. PPARα expression was analysed in livers from elective surgery and critically ill patients and correlated with hepatic gene expression and blood parameters RESULTS: Both whole body and non-hematopoietic Pparα-deficiency in mice decreased survival upon bacterial infection. Livers of septic Pparα-deficient mice displayed an impaired metabolic shift from glucose to lipid utilization resulting in more severe hypoglycemia, impaired induction of hyperketonemia and increased steatosis due to lower expression of genes involved in fatty acid catabolism and ketogenesis. Hepatocyte-specific deletion of PPARα impaired the metabolic response to sepsis and was sufficient to decrease survival upon bacterial infection. Hepatic PPARA expression was lower in critically ill patients and correlated positively with expression of lipid metabolism genes, but not with systemic inflammatory markers.Metabolic control by PPARα in hepatocytes plays a key role in the host defense to infection. Lay summary: As the main cause of death of critically ill patients, sepsis remains a major health issue lacking efficacious therapies. While current clinical literature suggests an important role for inflammation, metabolic aspects of sepsis have been mostly overlooked. Here, we show that mice with an impaired metabolic response, due to deficiency of the nuclear receptor PPARα in the liver, exhibit enhanced mortality upon bacterial infection despite a similar inflammatory response, suggesting that metabolic interventions may be a viable strategy for improving sepsis outcomes.Copyright © 2019. Published by Elsevier B.V.right © 2019. Published by Elsevier B.V.)
Richards 2014 Surg Obes Relat Dis + (Although the salutary effects of bariatric … Although the salutary effects of bariatric surgery as a treatment for excess weight and type 2 diabetes are established, there is scant evidence for effects on other contributors to cardiovascular diseases such as repair of endothelial dysfunction. This study evaluates outcomes of bariatric surgery on late outgrowth endothelial progenitor cells (LOEPCs), a cell phenotype essential for endothelial repair.Patients with a body mass index >35 kg/m(2) and type 2 diabetes were enrolled into either medical or bariatric surgical arms. Primary outcomes included analysis of isolated LOEPCs from peripheral blood for growth, function, and mitochondrial respiration. Plasma was used for metabolic profiling.Medical arm patients showed no improvement in any of the parameters tested. Bariatric surgical arm patients showed a 24% reduction in body mass index as early as 3 months postintervention and resolution of type 2 diabetes at 24 months postintervention (HbA1c 31% reduction; fasting glucose 29% reduction). Bariatric surgery increased the numbers of LOEPCs 8-fold and increased LOEPC network formation 3-fold at 24 months postintervention. The increased numbers and activity of LOEPCs in the bariatric surgical arm correlated with improvements in body mass index, insulin, and triglyceride levels only at 24 month postintervention. LOEPC mitochondrial respiration displayed a trend toward improvement compared with baseline as evidenced by an increase (36%) at 24 months in the bariatric arm.Bariatric surgery increases LOEPC levels and activity, which correlates with weight loss and improved metabolic profile at 24 months postintervention.abolic profile at 24 months postintervention.)
Layec 2016 Am J Physiol Endocrinol Metab + (Although theoretically sound, the accuracy … Although theoretically sound, the accuracy and precision of (31)P-magnetic resonance spectroscopy ((31)P-MRS) approaches to quantitatively estimate mitochondrial capacity are not well documented. Therefore, employing four differing models of respiratory control [linear, kinetic, and multipoint adenosine diphosphate (ADP) and phosphorylation potential], this study sought to determine the accuracy and precision of (31)P-MRS assessments of peak mitochondrial adenosine-triphosphate (ATP) synthesis rate utilizing directly measured peak respiration (State 3) in permeabilized skeletal muscle fibers. In 23 subjects of different fitness levels, (31)P-MRS during a 24-s maximal isometric knee extension and high-resolution respirometry in muscle fibers from the vastus lateralis was performed. Although significantly correlated with State 3 respiration (r = 0.72), both the linear (45 ± 13 mM/min) and phosphorylation potential (47 ± 16 mM/min) models grossly overestimated the calculated ''in vitro'' peak ATP synthesis rate (P < 0.05). Of the ADP models, the kinetic model was well correlated with State 3 respiration (r = 0.72, P < 0.05), but moderately overestimated ATP synthesis rate (P < 0.05), while the multipoint model, although being somewhat less well correlated with State 3 respiration (r = 0.55, P < 0.05), most accurately reflected peak ATP synthesis rate. Of note, the PCr recovery time constant (τ), a qualitative index of mitochondrial capacity, exhibited the strongest correlation with State 3 respiration (r = 0.80, P < 0.05). Therefore, this study reveals that each of the (31)P-MRS data analyses, including PCr τ, exhibit precision in terms of mitochondrial capacity. As only the multipoint ADP model did not overstimate the peak skeletal muscle mitochondrial ATP synthesis, the multipoint ADP model is the only quantitative approach to exhibit both accuracy and precision.titative approach to exhibit both accuracy and precision.)
Luo 2018 Proc Natl Acad Sci U S A + (Although there has been considerable debat … Although there has been considerable debate about whether paternal mitochondrial DNA (mtDNA) transmission may coexist with maternal transmission of mtDNA, it is generally believed that mitochondria and mtDNA are exclusively maternally inherited in humans. Here, we identified three unrelated multigeneration families with a high level of mtDNA heteroplasmy (ranging from 24 to 76%) in a total of 17 individuals. Heteroplasmy of mtDNA was independently examined by high-depth whole mtDNA sequencing analysis in our research laboratory and in two Clinical Laboratory Improvement Amendments and College of American Pathologists-accredited laboratories using multiple approaches. A comprehensive exploration of mtDNA segregation in these families shows biparental mtDNA transmission with an autosomal dominantlike inheritance mode. Our results suggest that, although the central dogma of maternal inheritance of mtDNA remains valid, there are some exceptional cases where paternal mtDNA could be passed to the offspring. Elucidating the molecular mechanism for this unusual mode of inheritance will provide new insights into how mtDNA is passed on from parent to offspring and may even lead to the development of new avenues for the therapeutic treatment for pathogenic mtDNA transmission.eatment for pathogenic mtDNA transmission.)
Driescher 2019 Heliyon + (Although there is evidence linking sugar-s … Although there is evidence linking sugar-sweetened beverage (SSB) intake with the development of cardio-metabolic diseases, the underlying mechanisms remain unclear. The current study therefore evaluated the effects of SSB consumption by establishing a unique in-house ''in vivo'' experimental model.Male Wistar rats were divided into two groups: a) one consuming a popular local SSB (SSB- Jive), and b) a control group (Control-water) for a period of three and six months (n = 6 per group), respectively. Rats were gavaged on a daily basis with an experimental dosage amounting to half a glass per day (in human terms) (SSB vs. water). Cardiac function was assessed at baseline (echocardiography) and following ''ex vivo'' ischemia-reperfusion of the isolated perfused working rat heart. Oral glucose tolerance tests and mitochondrial respiratory analyses were also performed. In addition, the role of non-oxidative glucose pathways (NOGPs), i.e. the polyol pathway, hexosamine biosynthetic pathway (HBP) and PKC were assessed.These data show that SSB intake: a) resulted in increased weight gain, but did not elicit major effects in terms of insulin resistance and cardiac function after three and six months, respectively; b) triggered myocardial NOGP activation after three months with a reversion after six months; and c) resulted in some impairment in mitochondrial respiratory capacity in response to fatty acid substrate supply after six months.SSB intake did not result in cardiac dysfunction or insulin resistance. However, early changes at the molecular level may increase risk in the longer term.evel may increase risk in the longer term.)
Acuña-Castroviejo 2011 Curr Top Med Chem + (Although two main hypotheses of mitochondr … Although two main hypotheses of mitochondrial origin have been proposed, i.e., the autogenous and the endosymbiotic, only the second is being seriously considered currently. The 'hydrogen hypothesis' invokes metabolic symbiosis as the driving force for a symbiotic association between an anaerobic, strictly hydrogen-dependent (the host) and an eubacterium (the symbiont) that was able to respire, but which generated molecular hydrogen as an end product of anaerobic metabolism. The resulting proto-eukaryotic cell would have acquired the essentials of eukaryotic energy metabolism, evolving not only aerobic respiration, but also the physiological cost of the oxygen consumption, i.e., generation of reactive oxygen species (ROS) and the associated oxidative damage. This is not the only price to pay for respiring oxygen: mitochondria possess nitric oxide (NO·) for regulatory purposes but, in some instances it may react with superoxide anion radical to produce the toxic reactive nitrogen species (RNS), i.e. peroxynitrite anion, and the subsequent nitrosative damage. New mitochondria contain their own genome with a modified genetic code that is highly conserved among mammals. The transcription of certain mitochondrial genes may depend on the redox potential of the mitochondrial membrane. Mitochondria are related to the life and death of cells. They are involved in energy production and conservation, having an uncoupling mechanism to produce heat instead of ATP, but they are also involved in programmed cell death. Increasing evidence suggest the participation of mitochondria in neurodegenerative and neuromuscular diseases involving alterations in both nuclear (nDNA) and mitochondrial (mtDNA) DNA. Melatonin is a known powerful antioxidant and anti-inflammatory and increasing experimental and clinical evidence shows its beneficial effects against oxidative/nitrosative stress status, including that involving mitochondrial dysfunction. This review summarizes the data and mechanisms of action of melatonin in relation to mitochondrial pathologies. in relation to mitochondrial pathologies.)
Vicentini 2019 Plant Physiol Biochem + (Aluminum (Al) toxicity has been recognized … Aluminum (Al) toxicity has been recognized to be a main limiting factor of crop productivity in acid soil. Al interacts with cell walls disrupting the functions of the plasma membrane and is associated with oxidative damage and mitochondrial dysfunction. ''Jatropha curcas'' L. (''J. curcas'') is a drought resistant plant, widely distributed around the world, with great economic and medicinal importance. Here we investigated the effects of Al on ''J. curcas'' mitochondrial function and cell viability, analyzing mitochondrial respiration, phenolic compounds, reducing sugars and cell viability in cultured ''J. curcas'' cells. The results showed that at 70 μM, Al limited mitochondrial respiration by inhibiting the alternative oxidase (AOX) pathway in the respiratory chain. An increased concentration of reducing sugars and reduced concentration of intracellular phenolic compounds was observed during respiratory inhibition. After inhibition, a time-dependent upregulation of AOX mRNA was observed followed by restoration of respiratory activity and reducing sugar concentrations. Cultured ''J. curcas'' cells were very resistant to Al-induced cell death. In addition, at 70 μM, Al also appeared as an inhibitor of cell wall invertase. In conclusion, Al tolerance in cultured ''J. curcas'' cells involves a inhibition of mitochondrial AOX pathway, which seems to start an oxidative burst to induce AOX upregulation, which in turn restores consumption of O2 and substrates. These data provide new insight into the signaling cascades that modulate the Al tolerance mechanism.Copyright © 2019 Elsevier Masson SAS. All rights reserved.ght © 2019 Elsevier Masson SAS. All rights reserved.)
Vicentini 2019 Plant Physiol Biochim + (Aluminum (Al) toxicity has been recognized … Aluminum (Al) toxicity has been recognized to be a main limiting factor of crop productivity in acid soil. Al interacts with cell walls disrupting the functions of the plasma membrane and is associated with oxidative damage and mitochondrial dysfunction. ''Jatropha curcas'' L. (J. curcas) is a drought resistant plant, widely distributed around the world, with great economic and medicinal importance. Here we investigated the effects of Al on ''J. curcas'' mitochondrial function and cell viability, analyzing mitochondrial respiration, phenolic compounds, reducing sugars and cell viability in cultured ''J. curcas'' cells. The results showed that at 70 μM, Al limited mitochondrial respiration by inhibiting the alternative oxidase (AOX) pathway in the respiratory chain. An increased concentration of reducing sugars and reduced concentration of intracellular phenolic compounds was observed during respiratory inhibition. After inhibition, a time-dependent upregulation of AOX mRNA was observed followed by restoration of respiratory activity and reducing sugar concentrations. Cultured ''J. curcas'' cells were very resistant to Al-induced cell death. In addition, at 70 μM, Al also appeared as an inhibitor of cell wall invertase. In conclusion, Al tolerance in cultured ''J. curcas'' cells involves a inhibition of mitochondrial AOX pathway, which seems to start an oxidative burst to induce AOX upregulation, which in turn restores consumption of O2 and substrates. These data provide new insight into the signaling cascades that modulate the Al tolerance mechanism. that modulate the Al tolerance mechanism.)
Stojakovic 2021 Commun Biol + (Alzheimer's Disease (AD) is a devastating … Alzheimer's Disease (AD) is a devastating neurodegenerative disorder without a cure. Here we show that mitochondrial respiratory chain complex I is an important small molecule druggable target in AD. Partial inhibition of complex I triggers the AMP-activated protein kinase-dependent signaling network leading to neuroprotection in symptomatic APP/PS1 female mice, a translational model of AD. Treatment of symptomatic APP/PS1 mice with complex I inhibitor improved energy homeostasis, synaptic activity, long-term potentiation, dendritic spine maturation, cognitive function and proteostasis, and reduced oxidative stress and inflammation in brain and periphery, ultimately blocking the ongoing neurodegeneration. Therapeutic efficacy ''in vivo'' was monitored using translational biomarkers FDG-PET, 31P NMR, and metabolomics. Cross-validation of the mouse and the human transcriptomic data from the NIH Accelerating Medicines Partnership-AD database demonstrated that pathways improved by the treatment in APP/PS1 mice, including the immune system response and neurotransmission, represent mechanisms essential for therapeutic efficacy in AD patients.l for therapeutic efficacy in AD patients.)
Lim 2010 Proteomics + (Alzheimer's disease (AD) and type 2 diabet … Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are leading causes of morbidity and mortality in the elderly. Both diseases are characterized by amyloid deposition in target tissues: aggregation of amylin in T2DM is associated with loss of insulin-secreting beta-cells, while amyloid beta (A beta) aggregation in AD brain is associated with neuronal loss. Here, we used quantitative iTRAQ proteomics as a discovery tool to show that both A beta and human amylin (HA) deregulate identical proteins, a quarter of which are mitochondrial, supporting the notion that mitochondrial dysfunction is a common target in these two amyloidoses. A functional validation revealed that mitochondrial complex IV activity was significantly reduced after treatment with either HA or A beta, as was mitochondrial respiration. In comparison, complex I activity was reduced only after treatment with HA. A beta and HA, but not the non-amyloidogenic rat amylin, induced significant increases in the generation of ROS. Co-incubation of HA and A beta did not produce an augmented effect in ROS production, again suggesting common toxicity mechanisms. In conclusion, our data suggest that A beta and HA both exert toxicity, at least in part, via mitochondrial dysfunction, thus restoring their function may be beneficial for both AD and T2DM.on may be beneficial for both AD and T2DM.)
Lim 2011 PloS One + (Alzheimer's disease (AD) is a conformation … Alzheimer's disease (AD) is a conformational disease that is characterized by amyloid-β (Aβ) deposition in the brain. Aβ exerts its toxicity in part by receptor-mediated interactions that cause down-stream protein misfolding and aggregation, as well as mitochondrial dysfunction. Recent reports indicate that Aβ may also interact directly with intracellular proteins such as the mitochondrial enzyme ABAD (Aβ binding alcohol dehydrogenase) in executing its toxic effects. Mitochondrial dysfunction occurs early in AD, and Aβ's toxicity is in part mediated by inhibition of ABAD as shown previously with an ABAD decoy peptide. Here, we employed AG18051, a novel small ABAD-specific compound inhibitor, to investigate the role of ABAD in Aβ toxicity. Using SH-SY5Y neuroblastoma cells, we found that AG18051 partially blocked the Aβ-ABAD interaction in a pull-down assay while it also prevented the Aβ42-induced down-regulation of ABAD activity, as measured by levels of estradiol, a known hormone and product of ABAD activity. Furthermore, AG18051 is protective against Aβ42 toxicity, as measured by LDH release and MTT absorbance. Specifically, AG18051 reduced Aβ42-induced impairment of mitochondrial respiration and oxidative stress as shown by reduced ROS (reactive oxygen species) levels. Guided by our previous finding of shared aspects of the toxicity of Aβ and human amylin (HA), with the latter forming aggregates in Type 2 diabetes mellitus (T2DM) pancreas, we determined whether AG18051 would also confer protection from HA toxicity. We found that the inhibitor conferred only partial protection from HA toxicity indicating distinct pathomechanisms of the two amyloidogenic agents. Taken together, our results present the inhibition of ABAD by compounds such as AG18051 as a promising therapeutic strategy for the prevention and treatment of AD, and suggest levels of estradiol as a suitable read-out.evels of estradiol as a suitable read-out.)
Onukwufor 2022 Antioxidants (Basel) + (Alzheimer's disease (AD) is a devastating … Alzheimer's disease (AD) is a devastating progressive neurodegenerative disease characterized by neuronal dysfunction, and decreased memory and cognitive function. Iron is critical for neuronal activity, neurotransmitter biosynthesis, and energy homeostasis. Iron accumulation occurs in AD and results in neuronal dysfunction through activation of multifactorial mechanisms. Mitochondria generate energy and iron is a key co-factor required for: (1) ATP production by the electron transport chain, (2) heme protein biosynthesis and (3) iron-sulfur cluster formation. Disruptions in iron homeostasis result in mitochondrial dysfunction and energetic failure. Ferroptosis, a non-apoptotic iron-dependent form of cell death mediated by uncontrolled accumulation of reactive oxygen species and lipid peroxidation, is associated with AD and other neurodegenerative diseases. AD pathogenesis is complex with multiple diverse interacting players including Aβ-plaque formation, phosphorylated tau, and redox stress. Unfortunately, clinical trials in AD based on targeting these canonical hallmarks have been largely unsuccessful. Here, we review evidence linking iron dysregulation to AD and the potential for targeting ferroptosis as a therapeutic intervention for AD.osis as a therapeutic intervention for AD.)
De Godoy 2018 J Biol Chem + (Alzheimer's disease (AD) is a disabling an … Alzheimer's disease (AD) is a disabling and highly prevalent neurodegenerative condition, for which there are no effective therapies. Soluble oligomers of the amyloid-β peptide (AβOs) are thought to be proximal neurotoxins involved in early neuronal oxidative stress and synapse damage, ultimately leading to neurodegeneration and memory impairment in AD. The aim of the current study was to evaluate the neuroprotective potential of mesenchymal stem cells (MSCs) against the deleterious impact of AβOs on hippocampal neurons. To this end, we established transwell cocultures of rat hippocampal neurons and MSCs. We show that MSCs and MSC-derived extracellular vesicles protect neurons against AβO-induced oxidative stress and synapse damage, revealed by loss of pre- and postsynaptic markers. Protection by MSCs entails three complementary mechanisms: 1) internalization and degradation of AβOs; 2) release of extracellular vesicles containing active catalase; and 3) selective secretion of interleukin-6, interleukin-10, and vascular endothelial growth factor to the medium. Results support the notion that MSCs may represent a promising alternative for cell-based therapies in AD.lternative for cell-based therapies in AD.)
Martins 2017 Thesis + (Alzheimer's disease (AD) is a neurological … Alzheimer's disease (AD) is a neurological disorder that affects a large part of the world's population. It is characterized by memory loss, progressive dementia, behavioral changes and inability to perform routine activities. Histopathologically, AD presents the formation of plaques by the aggregation of amyloid-β peptides (Aβ) and neurofibrillary tangles, due to hyperphosphorylation of tau protein. The aim of this study was to investigate alterations in gene and protein expression related to AD and to evaluate the mechanisms involved in initial events of Aβ1-40 peptide toxicity after intracerebroventricular (i.c.v.) infusion. In addition, it was evaluated whether pre-treatment with atorvastatin prevents the toxic effects of this peptide. Adult male Swiss albino mice (3 months / 40-50g) were treated with atorvastatin 10 mg / kg / day, orally, or vehicle (0.9% saline) for 7 days. On the seventh day the aggregate form of Aβ1-40 (i.c.v., 400pmol / site) or saline was administered. After 24h, the animals were euthanized for biochemical analysis. The results show that atorvastatin is able to prevent the gene expression reduction of the postsynaptic protein PSD-95, the NMDA receptor GluN1 subunit and glutamatergic transporters GLAST and GLT-1 induced by Aβ1-40 infusion in the hippocampus. Aβ promoted a decrease in BDNF expression and an increase in reactive oxygen (ROS) and nitrogen (RNS) species levels. Pretreatment with atorvastatin was able to prevent the increased ROS and RNS. Through the evaluation of mitochondrial functionality by high resolution respirometry, we observed that Aβ1-40 did not significantly alter parameters of oxygen consumption. However, atorvastatin increased the mitochondrial respiratory capacity assessed in hippocampal homogenates. In conclusion, we observed that Aβ1-40 toxicity presents as initial events changes in proteins related to glutamatergic neurotransmission and oxidative stress. Atorvastatin prevents initial oxidative stress and increases mitochondrial respiratory capacity by an as yet unknown action mechanism, requiring further studies.s mitochondrial respiratory capacity by an as yet unknown action mechanism, requiring further studies.)
Rhein 2009 Proc Natl Acad Sci U S A + (Alzheimer's disease (AD) is characterized … Alzheimer's disease (AD) is characterized by amyloid-beta (Abeta)-containing plaques, neurofibrillary tangles, and neuron and synapse loss. Tangle formation has been reproduced in P301L tau transgenic pR5 mice, whereas APPswPS2N141I double-transgenic APP152 mice develop Abeta plaques. Cross-breeding generates triple transgenic (tripleAD) mice that combine both pathologies in one model. To determine functional consequences of the combined Abeta and tau pathologies, we performed a proteomic analysis followed by functional validation. Specifically, we obtained vesicular preparations from tripleAD mice, the parental strains, and nontransgenic mice, followed by the quantitative mass-tag labeling proteomic technique iTRAQ and mass spectrometry. Within 1,275 quantified proteins, we found a massive deregulation of 24 proteins, of which one-third were mitochondrial proteins mainly related to complexes I and IV of the oxidative phosphorylation system (OXPHOS). Notably, deregulation of complex I was tau dependent, whereas deregulation of complex IV was Abeta dependent, both at the protein and activity levels. Synergistic effects of Abeta and tau were evident in 8-month-old tripleAD mice as only they showed a reduction of the mitochondrial membrane potential at this early age. At the age of 12 months, the strongest defects on OXPHOS, synthesis of ATP, and reactive oxygen species were exhibited in the tripleAD mice, again emphasizing synergistic, age-associated effects of Abeta and tau in perishing mitochondria. Our study establishes a molecular link between Abeta and tau protein in AD pathology in vivo, illustrating the potential of quantitative proteomics.link between Abeta and tau protein in AD pathology in vivo, illustrating the potential of quantitative proteomics.)
Grimm 2016 Methods Mol Biol + (Alzheimer's disease (AD) is characterized … Alzheimer's disease (AD) is characterized by the presence of amyloid plaques (aggregates of amyloid-β [Aβ]) and neurofibrillary tangles (aggregates of tau) in the brain, but the underlying mechanisms of the disease are still partially unclear. A growing body of evidence supports mitochondrial dysfunction as a prominent and early, chronic oxidative stress-associated event that contributes to synaptic abnormalities, and, ultimately, selective neuronal degeneration in AD. Using a high-resolution respirometry system, we shed new light on the close interrelationship of this organelle with Aβ and tau in the pathogenic process underlying AD by showing a synergistic effect of these two hallmark proteins on the oxidative phosphorylation capacity of mitochondria isolated from the brain of transgenic AD mice. In the present chapter, we first introduce the principle of the Aβ and tau interaction on mitochondrial respiration, and secondly, we describe in detail the used respiratory protocol.e in detail the used respiratory protocol.)
Leuner 2012 Mol Neurobiol + (Alzheimer's disease (AD) is the most commo … Alzheimer's disease (AD) is the most common progressive neurodegenerative disease. Today, AD affects millions of people worldwide and the number of AD cases will increase with increased life expectancy. The AD brain is marked by severe neurodegeneration like the loss of synapses and neurons, atrophy and depletion of neurotransmitter systems in the hippocampus and cerebral cortex. Recent findings suggest that these pathological changes are causally induced by mitochondrial dysfunction and increased oxidative stress. These changes are not only observed in the brain of AD patients but also in the periphery. In this review, we discuss the potential role of elevated apoptosis, increased oxidative stress and especially mitochondrial dysfunction as peripheral markers for the detection of AD in blood cells especially in lymphocytes. We discuss recent not otherwise published findings on the level of complex activities of the respiratory chain comprising mitochondrial respiration and the mitochondrial membrane potential (MMP). We obtained decreased basal MMP levels in lymphocytes from AD patients as well as enhanced sensitivity to different complex inhibitors of the respiratory chain. These changes are in line with mitochondrial defects obtained in AD cell and animal models, and in post-mortem AD tissue. Importantly, these mitochondrial alterations where not only found in AD patients but also in patients with mild cognitive impairment (MCI). These new findings point to a relevance of mitochondrial function as an early peripheral marker for the detection of AD and MCI.al marker for the detection of AD and MCI.)