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Mitochondrial DNA depletion by ethidium bromide decreases neuronal mitochondrial creatine kinase: Implications for striatal energy metabolism.
Warren EB, Aicher AE, Fessel JP, Konradi C
(2017) PLoS One 12: e0190456
MeSH Terms: Animals, Cells, Cultured, Corpus Striatum, Creatine Kinase, DNA, Mitochondrial, Energy Metabolism, Ethidium, Glycolysis, Humans, Mitochondria, Oxygen Consumption, Rats, Rats, Sprague-Dawley
Show Abstract · Added March 14, 2018
Mitochondrial DNA (mtDNA), the discrete genome which encodes subunits of the mitochondrial respiratory chain, is present at highly variable copy numbers across cell types. Though severe mtDNA depletion dramatically reduces mitochondrial function, the impact of tissue-specific mtDNA reduction remains debated. Previously, our lab identified reduced mtDNA quantity in the putamen of Parkinson's Disease (PD) patients who had developed L-DOPA Induced Dyskinesia (LID), compared to PD patients who had not developed LID and healthy subjects. Here, we present the consequences of mtDNA depletion by ethidium bromide (EtBr) treatment on the bioenergetic function of primary cultured neurons, astrocytes and neuron-enriched cocultures from rat striatum. We report that EtBr inhibition of mtDNA replication and transcription consistently reduces mitochondrial oxygen consumption, and that neurons are significantly more sensitive to EtBr than astrocytes. EtBr also increases glycolytic activity in astrocytes, whereas in neurons it reduces the expression of mitochondrial creatine kinase mRNA and levels of phosphocreatine. Further, we show that mitochondrial creatine kinase mRNA is similarly downregulated in dyskinetic PD patients, compared to both non-dyskinetic PD patients and healthy subjects. Our data support a hypothesis that reduced striatal mtDNA contributes to energetic dysregulation in the dyskinetic striatum by destabilizing the energy buffering system of the phosphocreatine/creatine shuttle.
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13 MeSH Terms
Metabolic Effects of Diet and Exercise in Patients with Moderate to Severe CKD: A Randomized Clinical Trial.
Ikizler TA, Robinson-Cohen C, Ellis C, Headley SAE, Tuttle K, Wood RJ, Evans EE, Milch CM, Moody KA, Germain M, Limkunakul C, Bian A, Stewart TG, Himmelfarb J
(2018) J Am Soc Nephrol 29: 250-259
MeSH Terms: Adiposity, Aged, Albuminuria, Body Weight, Caloric Restriction, Creatinine, Exercise, F2-Isoprostanes, Female, Glomerular Filtration Rate, Humans, Interleukin-6, Male, Middle Aged, Oxidative Stress, Oxygen Consumption, Pilot Projects, Renal Insufficiency, Chronic
Show Abstract · Added October 24, 2017
CKD is steadily increasing along with obesity worldwide. Furthermore, obesity is a proinflammatory risk factor for progression of CKD and cardiovascular disease. We tested the hypothesis that implementation of caloric restriction and aerobic exercise is feasible and can improve the proinflammatory metabolic milieu in patients with moderate to severe CKD through a pilot, randomized, 2×2 factorial design trial. Of 122 participants consented, 111 were randomized to receive caloric restriction and aerobic exercise, caloric restriction alone, aerobic exercise alone, or usual care. Of those randomized, 42% were women, 25% were diabetic, and 91% were hypertensive; 104 started intervention, and 92 completed the 4-month study. Primary outcomes were a change from baseline in absolute fat mass, body weight, plasma F-isoprostane concentrations, and peak oxygen uptake (VO). Compared with usual care, the combined intervention led to statistically significant decreases in body weight and body fat percentage. Caloric restriction alone also led to significant decreases in these measures, but aerobic exercise alone did not. The combined intervention and each independent intervention also led to significant decreases in F-isoprostane and IL-6 concentrations. No intervention produced significant changes in VO, kidney function, or urine albumin-to-creatinine ratio. In conclusion, 4-month dietary calorie restriction and aerobic exercise had significant, albeit clinically modest, benefits on body weight, fat mass, and markers of oxidative stress and inflammatory response in patients with moderate to severe CKD. These results suggest healthy lifestyle interventions as a nonpharmacologic strategy to improve markers of metabolic health in these patients.
Copyright © 2018 by the American Society of Nephrology.
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18 MeSH Terms
Mitochondrial dysfunction in the APP/PSEN1 mouse model of Alzheimer's disease and a novel protective role for ascorbate.
Dixit S, Fessel JP, Harrison FE
(2017) Free Radic Biol Med 112: 515-523
MeSH Terms: Adenosine Diphosphate, Adenosine Triphosphate, Alzheimer Disease, Amyloid beta-Protein Precursor, Animals, Antioxidants, Ascorbic Acid, Biological Transport, Disease Models, Animal, Female, Gene Expression Regulation, Heterozygote, Humans, Male, Membrane Potential, Mitochondrial, Mice, Mice, Transgenic, Mitochondria, Mutation, Oxidative Stress, Oxygen Consumption, Presenilin-1, Reactive Oxygen Species, Signal Transduction, Sodium-Coupled Vitamin C Transporters
Show Abstract · Added March 14, 2018
Mitochondrial dysfunction is elevated in very early stages of Alzheimer's disease and exacerbates oxidative stress, which contributes to disease pathology. Mitochondria were isolated from 4-month-old wild-type mice, transgenic mice carrying the APP and PSEN1 mutations, mice with decreased brain and mitochondrial ascorbate (vitamin C) via heterozygous knockout of the sodium dependent vitamin C transporter (SVCT2) and transgenic APP/PSEN1 mice with heterozygous SVCT2 expression. Mitochondrial isolates from SVCT2 mice were observed to consume less oxygen using high-resolution respirometry, and also exhibited decreased mitochondrial membrane potential compared to wild type isolates. Conversely, isolates from young (4 months) APP/PSEN1 mice consumed more oxygen, and exhibited an increase in mitochondrial membrane potential, but had a significantly lower ATP/ADP ratio compared to wild type isolates. Greater levels of reactive oxygen species were also produced in mitochondria isolated from both APP/PSEN1 and SVCT2 mice compared to wild type isolates. Acute administration of ascorbate to mitochondria isolated from wild-type mice increased oxygen consumption compared with untreated mitochondria suggesting ascorbate may support energy production. This study suggests that both presence of amyloid and ascorbate deficiency can contribute to mitochondrial dysfunction, even at an early, prodromal stage of Alzheimer's disease, although occurring via different pathways. Ascorbate may, therefore, provide a useful preventative strategy against neurodegenerative disease, particularly in populations most at risk for Alzheimer's disease in which stores are often depleted through mitochondrial dysfunction and elevated oxidative stress.
Copyright © 2017 Elsevier Inc. All rights reserved.
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25 MeSH Terms
Oxygenation Saturation Index Predicts Clinical Outcomes in ARDS.
DesPrez K, McNeil JB, Wang C, Bastarache JA, Shaver CM, Ware LB
(2017) Chest 152: 1151-1158
MeSH Terms: Biomarkers, Female, Follow-Up Studies, Humans, Male, Middle Aged, Oximetry, Oxygen, Oxygen Consumption, Predictive Value of Tests, Prospective Studies, Respiratory Distress Syndrome, Adult, Severity of Illness Index
Show Abstract · Added May 31, 2018
BACKGROUND - Traditional measures of ARDS severity such as Pao/Fio may not reliably predict clinical outcomes. The oxygenation index (OI [Fio × mean airway pressure × 100)/Pao]) may more accurately reflect ARDS severity but requires arterial blood gas measurement. We hypothesized that the oxygenation saturation index (OSI [Fio × mean airway pressure × 100)/oxygen saturation by pulse oximetry (Spo)]) is a reliable noninvasive surrogate for the OI that is associated with hospital mortality and ventilator-free days (VFDs) in patients with ARDS.
METHODS - Critically ill patients enrolled in a prospective cohort study were eligible if they developed ARDS (Berlin criteria) during the first 4 ICU days and had mean airway pressure, Spo/Fio, and Pao/Fio values recorded on the first day of ARDS (N = 329). The highest mean airway pressure and lowest Spo/Fio and Pao/Fio values were used to calculate OI and OSI. The association between OI or OSI and hospital mortality or VFD was analyzed by using logistic regression and linear regression, respectively. The area under the receiver-operating characteristic curve (AUC) for mortality was compared among OI, OSI, Spo/Fio, Pao/Fio, and Acute Physiology and Chronic Health Evaluation II scores.
RESULTS - OI and OSI were strongly correlated (rho = 0.862; P < .001). OSI was independently associated with hospital mortality (OR per 5-point increase in OSI, 1.228 [95% CI, 1.056-1.429]; P = .008). OI and OSI were each associated with a reduction in VFD (OI, P = .023; OSI, P = .005). The AUC for mortality prediction was greatest for Acute Physiology and Chronic Health Evaluation II scores (AUC, 0.695; P < .005) and OSI (AUC, 0.602; P = .007). The AUC for OSI was substantially better in patients aged < 40 years (AUC, 0.779; P < .001).
CONCLUSIONS - In patients with ARDS, the OSI was correlated with the OI. The OSI on the day of ARDS diagnosis was significantly associated with increased mortality and fewer VFDs. The findings suggest that OSI is a reliable surrogate for OI that can noninvasively provide prognostic information and assessment of ARDS severity.
Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.
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Isotopically Nonstationary Metabolic Flux Analysis (INST-MFA) of Photosynthesis and Photorespiration in Plants.
Ma F, Jazmin LJ, Young JD, Allen DK
(2017) Methods Mol Biol 1653: 167-194
MeSH Terms: Amino Acids, Arabidopsis, Carbon Dioxide, Carbon Isotopes, Chlorophyll, Chloroplasts, Isotope Labeling, Mass Spectrometry, Metabolic Flux Analysis, Metabolic Networks and Pathways, Oxygen, Oxygen Consumption, Photosynthesis, Plant Leaves, Ribulose-Bisphosphate Carboxylase, Starch, Sucrose
Show Abstract · Added September 11, 2017
Photorespiration is a central component of photosynthesis; however to better understand its role it should be viewed in the context of an integrated metabolic network rather than a series of individual reactions that operate independently. Isotopically nonstationary C metabolic flux analysis (INST-MFA), which is based on transient labeling studies at metabolic steady state, offers a comprehensive platform to quantify plant central metabolism. In this chapter, we describe the application of INST-MFA to investigate metabolism in leaves. Leaves are an autotrophic tissue, assimilating CO over a diurnal period implying that the metabolic steady state is limited to less than 12 h and thus requiring an INST-MFA approach. This strategy results in a comprehensive unified description of photorespiration, Calvin cycle, sucrose and starch synthesis, tricarboxylic acid (TCA) cycle, and amino acid biosynthetic fluxes. We present protocols of the experimental aspects for labeling studies: transient CO labeling of leaf tissue, sample quenching and extraction, mass spectrometry (MS) analysis of isotopic labeling data, measurement of sucrose and amino acids in vascular exudates, and provide details on the computational flux estimation using INST-MFA.
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17 MeSH Terms
Hemodynamic mechanisms underlying elevated oxygen extraction fraction (OEF) in moyamoya and sickle cell anemia patients.
Watchmaker JM, Juttukonda MR, Davis LT, Scott AO, Faraco CC, Gindville MC, Jordan LC, Cogswell PM, Jefferson AL, Kirshner HS, Donahue MJ
(2018) J Cereb Blood Flow Metab 38: 1618-1630
MeSH Terms: Adult, Aged, Anemia, Sickle Cell, Cerebrovascular Circulation, Female, Hemodynamics, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Moyamoya Disease, Oxygen, Oxygen Consumption
Show Abstract · Added April 18, 2017
Moyamoya is a bilateral, complex cerebrovascular condition characterized by progressive non-atherosclerotic intracranial stenosis and collateral vessel formation. Moyamoya treatment focuses on restoring cerebral blood flow (CBF) through surgical revascularization, however stratifying patients for revascularization requires abilities to quantify how well parenchyma is compensating for arterial steno-occlusion. Globally elevated oxygen extraction fraction (OEF) secondary to CBF reduction may serve as a biomarker for tissue health in moyamoya patients, as suggested in patients with sickle cell anemia (SCA) and reduced oxygen carrying capacity. Here, OEF was measured (TRUST-MRI) to test the hypothesis that OEF is globally elevated in patients with moyamoya (n = 18) and SCA (n = 18) relative to age-matched controls (n = 43). Mechanisms underlying the hypothesized OEF increases were evaluated by performing sequential CBF-weighted, cerebrovascular reactivity (CVR)-weighted, and structural MRI. Patients were stratified by treatment and non-parametric tests applied to compare study variables (significance: two-sided P < 0.05). OEF was significantly elevated in moyamoya participants (interquartile range = 0.38-0.45) compared to controls (interquartile range = 0.29-0.38), similar to participants with SCA (interquartile range = 0.37-0.45). CBF was inversely correlated with OEF in moyamoya participants. Elevated OEF was only weakly related to reductions in CVR, consistent with basal CBF level, rather than vascular reserve capacity, being most closely associated with OEF.
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13 MeSH Terms
Post-contractile BOLD contrast in skeletal muscle at 7 T reveals inter-individual heterogeneity in the physiological responses to muscle contraction.
Towse TF, Elder CP, Bush EC, Klockenkemper SW, Bullock JT, Dortch RD, Damon BM
(2016) NMR Biomed 29: 1720-1728
MeSH Terms: Adult, Blood Flow Velocity, Blood Volume, Female, Humans, Magnetic Resonance Imaging, Male, Muscle Contraction, Muscle, Skeletal, Oxygen, Oxygen Consumption, Physical Endurance, Reproducibility of Results, Sensitivity and Specificity
Show Abstract · Added October 24, 2018
Muscle blood oxygenation-level dependent (BOLD) contrast is greater in magnitude and potentially more influenced by extravascular BOLD mechanisms at 7 T than it is at lower field strengths. Muscle BOLD imaging of muscle contractions at 7 T could, therefore, provide greater or different contrast than at 3 T. The purpose of this study was to evaluate the feasibility of using BOLD imaging at 7 T to assess the physiological responses to in vivo muscle contractions. Thirteen subjects (four females) performed a series of isometric contractions of the calf muscles while being scanned in a Philips Achieva 7 T human imager. Following 2 s maximal isometric plantarflexion contractions, BOLD signal transients ranging from 0.3 to 7.0% of the pre-contraction signal intensity were observed in the soleus muscle. We observed considerable inter-subject variability in both the magnitude and time course of the muscle BOLD signal. A subset of subjects (n = 7) repeated the contraction protocol at two different repetition times (T : 1000 and 2500 ms) to determine the potential of T -related inflow effects on the magnitude of the post-contractile BOLD response. Consistent with previous reports, there was no difference in the magnitude of the responses for the two T values (3.8 ± 0.9 versus 4.0 ± 0.6% for T  = 1000 and 2500 ms, respectively; mean ± standard error). These results demonstrate that studies of the muscle BOLD responses to contractions are feasible at 7 T. Compared with studies at lower field strengths, post-contractile 7 T muscle BOLD contrast may afford greater insight into microvascular function and dysfunction.
Copyright © 2016 John Wiley & Sons, Ltd.
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Direct real-time quantification of mitochondrial oxidative phosphorylation efficiency in permeabilized skeletal muscle myofibers.
Lark DS, Torres MJ, Lin CT, Ryan TE, Anderson EJ, Neufer PD
(2016) Am J Physiol Cell Physiol 311: C239-45
MeSH Terms: Adenosine Diphosphate, Adenosine Triphosphate, Adenylate Kinase, Animals, Glucosephosphate Dehydrogenase, Hexokinase, Male, Mice, Mice, Inbred C57BL, Mitochondria, Muscle Fibers, Skeletal, NADP, Oxidative Phosphorylation, Oxygen Consumption
Show Abstract · Added October 17, 2016
Oxidative phosphorylation (OXPHOS) efficiency, defined as the ATP-to-O ratio, is a critical feature of mitochondrial function that has been implicated in health, aging, and disease. To date, however, the methods to measure ATP/O have primarily relied on indirect approaches or entail parallel rather than simultaneous determination of ATP synthesis and O2 consumption rates. The purpose of this project was to develop and validate an approach to determine the ATP/O ratio in permeabilized fiber bundles (PmFBs) from simultaneous measures of ATP synthesis (JATP) and O2 consumption (JO2 ) rates in real time using a custom-designed apparatus. JO2 was measured via a polarigraphic oxygen sensor and JATP via fluorescence using an enzyme-linked assay system (hexokinase II, glucose-6-phosphate dehydrogenase) linked to NADPH production. Within the dynamic linear range of the assay system, ADP-stimulated increases in steady-state JATP mirrored increases in steady-state JO2 (r(2) = 0.91, P < 0.0001, n = 57 data points). ATP/O ratio was less than one under low rates of respiration (15 μM ADP) but increased to more than two at moderate (200 μM ADP) and maximal (2,000 μM ADP) rates of respiration with an interassay coefficient of variation of 24.03, 16.72, and 11.99%, respectively. Absolute and relative (to mechanistic) ATP/O ratios were lower in PmFBs (2.09 ± 0.251, 84%) compared with isolated mitochondria (2.44 ± 0.124, 98%). ATP/O ratios in PmFBs were not affected by the activity of adenylate kinase or creatine kinase. These findings validate an enzyme-linked respiratory clamp system for measuring OXPHOS efficiency in PmFBs and provide evidence that OXPHOS efficiency increases as energy demand increases.
Copyright © 2016 the American Physiological Society.
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14 MeSH Terms
CKD and Muscle Mitochondrial Energetics.
Roshanravan B, Kestenbaum B, Gamboa J, Jubrias SA, Ayers E, Curtin L, Himmelfarb J, de Boer IH, Conley KE
(2016) Am J Kidney Dis 68: 658-659
MeSH Terms: Adenosine Triphosphate, Adult, Aged, Case-Control Studies, Energy Metabolism, Female, Humans, Magnetic Resonance Spectroscopy, Male, Middle Aged, Mitochondria, Muscle, Muscle, Skeletal, Optical Imaging, Oxygen Consumption, Renal Insufficiency, Chronic, Spectrum Analysis
Added October 28, 2016
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16 MeSH Terms
Renal epithelium regulates erythropoiesis via HIF-dependent suppression of erythropoietin.
Farsijani NM, Liu Q, Kobayashi H, Davidoff O, Sha F, Fandrey J, Ikizler TA, O'Connor PM, Haase VH
(2016) J Clin Invest 126: 1425-37
MeSH Terms: Animals, Epithelium, Erythropoiesis, Erythropoietin, Glucose, Kidney Tubules, Proximal, Mice, Mice, Transgenic, Oxygen Consumption, Transcription Factors, Von Hippel-Lindau Tumor Suppressor Protein
Show Abstract · Added April 20, 2016
The adult kidney plays a central role in erythropoiesis and is the main source of erythropoietin (EPO), an oxygen-sensitive glycoprotein that is essential for red blood cell production. Decreases of renal pO2 promote hypoxia-inducible factor 2-mediated (HIF-2-mediated) induction of EPO in peritubular interstitial fibroblast-like cells, which serve as the cellular site of EPO synthesis in the kidney. It is not clear whether HIF signaling in other renal cell types also contributes to the regulation of EPO production. Here, we used a genetic approach in mice to investigate the role of renal epithelial HIF in erythropoiesis. Specifically, we found that HIF activation in the proximal nephron via induced inactivation of the von Hippel-Lindau tumor suppressor, which targets the HIF-α subunit for proteasomal degradation, led to rapid development of hypoproliferative anemia that was associated with a reduction in the number of EPO-producing renal interstitial cells. Moreover, suppression of renal EPO production was associated with increased glucose uptake, enhanced glycolysis, reduced mitochondrial mass, diminished O2 consumption, and elevated renal tissue pO2. Our genetic analysis suggests that tubulointerstitial cellular crosstalk modulates renal EPO production under conditions of epithelial HIF activation in the kidney.
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11 MeSH Terms