Publications by authors named "Daniel A Beard"

131 Publications

Quantitative analysis of mitochondrial ATP synthesis.

Math Biosci 2021 Jun 17:108646. Epub 2021 Jun 17.

Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, 48109, MI, USA. Electronic address:

We present a computational framework for analyzing and simulating mitochondrial ATP synthesis using basic thermodynamic and kinetic principles. The framework invokes detailed descriptions of the thermodynamic driving forces associated with the processes of the electron transport chain, mitochondrial ATP synthetase, and phosphate and adenine nucleotide transporters. Assembling models of these discrete processes into an integrated model of mitochondrial ATP synthesis, we illustrate how to analyze and simulate in vitro respirometry experiments and how models identified from in vitro experimental data effectively explain cardiac respiratory control in vivo. Computer codes for these analyses are embedded as Python scripts in a Jupyter Book to facilitate easy adoption and modification of the concepts developed here. This accessible framework may also prove useful in supporting educational applications. All source codes are available on at https://beards-lab.github.io/QAMAS_book/.
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http://dx.doi.org/10.1016/j.mbs.2021.108646DOI Listing
June 2021

Hypoxic pulmonary vasoconstriction as a regulator of alveolar-capillary oxygen flux: A computational model of ventilation-perfusion matching.

PLoS Comput Biol 2021 May 6;17(5):e1008861. Epub 2021 May 6.

Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States of America.

The relationship between regional variabilities in airflow (ventilation) and blood flow (perfusion) is a critical determinant of gas exchange efficiency in the lungs. Hypoxic pulmonary vasoconstriction is understood to be the primary active regulator of ventilation-perfusion matching, where upstream arterioles constrict to direct blood flow away from areas that have low oxygen supply. However, it is not understood how the integrated action of hypoxic pulmonary vasoconstriction affects oxygen transport at the system level. In this study we develop, and make functional predictions with a multi-scale multi-physics model of ventilation-perfusion matching governed by the mechanism of hypoxic pulmonary vasoconstriction. Our model consists of (a) morphometrically realistic 2D pulmonary vascular networks to the level of large arterioles and venules; (b) a tileable lumped-parameter model of vascular fluid and wall mechanics that accounts for the influence of alveolar pressure; (c) oxygen transport accounting for oxygen bound to hemoglobin and dissolved in plasma; and (d) a novel empirical model of hypoxic pulmonary vasoconstriction. Our model simulations predict that under the artificial test condition of a uniform ventilation distribution (1) hypoxic pulmonary vasoconstriction matches perfusion to ventilation; (2) hypoxic pulmonary vasoconstriction homogenizes regional alveolar-capillary oxygen flux; and (3) hypoxic pulmonary vasoconstriction increases whole-lobe oxygen uptake by improving ventilation-perfusion matching.
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http://dx.doi.org/10.1371/journal.pcbi.1008861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130924PMC
May 2021

Quantification of Myocardial Creatine and Triglyceride Content in the Human Heart: Precision and Accuracy of in vivo Proton Magnetic Resonance Spectroscopy.

J Magn Reson Imaging 2021 08 10;54(2):411-420. Epub 2021 Feb 10.

Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.

Background: Proton magnetic resonance spectroscopy ( H-MRS) of the human heart is deemed to be a quantitative method to investigate myocardial metabolite content, but thorough validations of in vivo measurements against invasive techniques are lacking.

Purpose: To determine measurement precision and accuracy for quantifications of myocardial total creatine and triglyceride content with localized H-MRS.

Study Type: Test-retest repeatability and measurement validation study.

Subjects: Sixteen volunteers and 22 patients scheduled for open-heart aortic valve replacement or septal myectomy.

Field Strength/sequence: Prospectively ECG-triggered respiratory-gated free-breathing single-voxel point-resolved spectroscopy (PRESS) sequence at 3 T.

Assessment: Myocardial total creatine and triglyceride content were quantified relative to the total water content by fitting the H-MR spectra. Precision was assessed with measurement repeatability. Accuracy was assessed by validating in vivo H-MRS measurements against biochemical assays in myocardial tissue from the same subjects.

Statistical Tests: Intrasession and intersession repeatability was assessed using Bland-Altman analyses. Agreement between H-MRS measurements and biochemical assay was tested with regression analyses.

Results: The intersession repeatability coefficient for myocardial total creatine content was 41.8% with a mean value of 0.083% ± 0.020% of the total water signal, and 36.7% for myocardial triglyceride content with a mean value of 0.35% ± 0.13% of the total water signal. Ex vivo myocardial total creatine concentrations in tissue samples correlated with the in vivo myocardial total creatine content measured with H-MRS: n = 22, r = 0.44; P < 0.05. Likewise, ex vivo myocardial triglyceride concentrations correlated with the in vivo myocardial triglyceride content: n = 20, r = 0.50; P < 0.05.

Data Conclusion: We validated the use of localized H-MRS of the human heart at 3 T for quantitative assessments of in vivo myocardial tissue metabolite content by estimating the measurement precision and accuracy.

Level Of Evidence: 2 TECHNICAL EFFICACY STAGE: 2.
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http://dx.doi.org/10.1002/jmri.27531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277665PMC
August 2021

Impaired Myocardial Energetics Causes Mechanical Dysfunction in Decompensated Failing Hearts.

Function (Oxf) 2020 22;1(2):zqaa018. Epub 2020 Sep 22.

Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.

Cardiac mechanical function is supported by ATP hydrolysis, which provides the chemical-free energy to drive the molecular processes underlying cardiac pumping. Physiological rates of myocardial ATP consumption require the heart to resynthesize its entire ATP pool several times per minute. In the failing heart, cardiomyocyte metabolic dysfunction leads to a reduction in the capacity for ATP synthesis and associated free energy to drive cellular processes. Yet it remains unclear if and how metabolic/energetic dysfunction that occurs during heart failure affects mechanical function of the heart. We hypothesize that changes in phosphate metabolite concentrations (ATP, ADP, inorganic phosphate) that are associated with decompensation and failure have direct roles in impeding contractile function of the myocardium in heart failure, contributing to the whole-body phenotype. To test this hypothesis, a transverse aortic constriction (TAC) rat model of pressure overload, hypertrophy, and decompensation was used to assess relationships between metrics of whole-organ pump function and myocardial energetic state. A multiscale computational model of cardiac mechanoenergetic coupling was used to identify and quantify the contribution of metabolic dysfunction to observed mechanical dysfunction. Results show an overall reduction in capacity for oxidative ATP synthesis fueled by either fatty acid or carbohydrate substrates as well as a reduction in total levels of adenine nucleotides and creatine in myocardium from TAC animals compared to sham-operated controls. Changes in phosphate metabolite levels in the TAC rats are correlated with impaired mechanical function, consistent with the overall hypothesis. Furthermore, computational analysis of myocardial metabolism and contractile dynamics predicts that increased levels of inorganic phosphate in TAC compared to control animals kinetically impair the myosin ATPase crossbridge cycle in decompensated hypertrophy/heart failure.
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http://dx.doi.org/10.1093/function/zqaa018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552914PMC
September 2020

Potential role of intermittent functioning of baroreflexes in the etiology of hypertension in spontaneously hypertensive rats.

JCI Insight 2020 10 2;5(19). Epub 2020 Oct 2.

Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.

The spontaneously hypertensive rat (SHR) is a genetic model of primary hypertension with an etiology that includes sympathetic overdrive. To elucidate the neurogenic mechanisms underlying the pathophysiology of this model, we analyzed the dynamic baroreflex response to spontaneous fluctuations in arterial pressure in conscious SHRs, as well as in the Wistar-Kyoto (WKY), the Dahl salt-sensitive, the Dahl salt-resistant, and the Sprague-Dawley rat. Observations revealed the existence of long intermittent periods (lasting up to several minutes) of engagement and disengagement of baroreflex control of heart rate. Analysis of these intermittent periods revealed a predictive relationship between increased mean arterial pressure and progressive baroreflex disengagement that was present in the SHR and WKY strains but absent in others. This relationship yielded the hypothesis that a lower proportion of engagement versus disengagement of the baroreflex in SHR compared with WKY contributes to the hypertension (or increased blood pressure) in SHR compared with WKY. Results of experiments using sinoaortic baroreceptor denervation were consistent with the hypothesis that dysfunction of the baroreflex contributes to the etiology of hypertension in the SHR. Thus, this study provides experimental evidence for the roles of the baroreflex in long-term arterial pressure regulation and in the etiology of primary hypertension in this animal model.
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http://dx.doi.org/10.1172/jci.insight.139789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566704PMC
October 2020

Endoplasmic reticulum-associated degradation regulates mitochondrial dynamics in brown adipocytes.

Science 2020 04 19;368(6486):54-60. Epub 2020 Mar 19.

Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48105, USA.

The endoplasmic reticulum (ER) engages mitochondria at specialized ER domains known as mitochondria-associated membranes (MAMs). Here, we used three-dimensional high-resolution imaging to investigate the formation of pleomorphic "megamitochondria" with altered MAMs in brown adipocytes lacking the Sel1L-Hrd1 protein complex of ER-associated protein degradation (ERAD). Mice with ERAD deficiency in brown adipocytes were cold sensitive and exhibited mitochondrial dysfunction. ERAD deficiency affected ER-mitochondria contacts and mitochondrial dynamics, at least in part, by regulating the turnover of the MAM protein, sigma receptor 1 (SigmaR1). Thus, our study provides molecular insights into ER-mitochondrial cross-talk and expands our understanding of the physiological importance of Sel1L-Hrd1 ERAD.
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http://dx.doi.org/10.1126/science.aay2494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409365PMC
April 2020

Age-Associated Mitochondrial Dysfunction Accelerates Atherogenesis.

Circ Res 2020 01 9;126(3):298-314. Epub 2019 Dec 9.

From the Department of Internal Medicine (D.J.T., M.G.B., J.S., S.C.W., D.R.G.), University of Michigan, Ann Arbor.

Aging is one of the strongest risk factors for atherosclerosis. Yet whether aging increases the risk of atherosclerosis independently of chronic hyperlipidemia is not known. To determine if vascular aging before the induction of hyperlipidemia enhances atherogenesis. We analyzed the aortas of young and aged normolipidemic wild type, disease-free mice and found that aging led to elevated IL (interleukin)-6 levels and mitochondrial dysfunction, associated with increased mitophagy and the associated protein Parkin. In aortic tissue culture, we found evidence that with aging mitochondrial dysfunction and IL-6 exist in a positive feedback loop. We triggered acute hyperlipidemia in aged and young mice by inducing liver-specific degradation of the LDL (low-density lipoprotein) receptor combined with a 10-week western diet and found that atherogenesis was enhanced in aged wild-type mice. Hyperlipidemia further reduced mitochondrial function and increased the levels of Parkin in the aortas of aged mice but not young mice. Genetic disruption of autophagy in smooth muscle cells of young mice exposed to hyperlipidemia led to increased aortic Parkin and IL-6 levels, impaired mitochondrial function, and enhanced atherogenesis. Importantly, enhancing mitophagy in aged, hyperlipidemic mice via oral administration of spermidine prevented the increase in aortic IL-6 and Parkin, attenuated mitochondrial dysfunction, and reduced atherogenesis. Before hyperlipidemia, aging elevates IL-6 and impairs mitochondrial function within the aorta, associated with enhanced mitophagy and increased Parkin levels. These age-associated changes prime the vasculature to exacerbate atherogenesis upon acute hyperlipidemia. Our work implies that novel therapeutics aimed at improving vascular mitochondrial bioenergetics or reducing inflammation before hyperlipidemia may reduce age-related atherosclerosis.
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http://dx.doi.org/10.1161/CIRCRESAHA.119.315644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7006722PMC
January 2020

The Heart by Numbers.

Biophys J 2019 12 29;117(12):E1-E3. Epub 2019 Nov 29.

Department of Medicine and Division of Cardiology, University of California, Los Angeles, Los Angeles, California.

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http://dx.doi.org/10.1016/j.bpj.2019.11.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990371PMC
December 2019

Cardiac Metabolic Limitations Contribute to Diminished Performance of the Heart in Aging.

Biophys J 2019 12 2;117(12):2295-2302. Epub 2019 Jul 2.

Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan. Electronic address:

Changes in the myocardial energetics associated with aging-reductions in creatine phosphate/ATP ratio, total creatine, and ATP-mirror changes observed in failing hearts compared to healthy controls. Similarly, both aging and heart failure are associated with significant reductions in cardiac performance and maximal left ventricular cardiac power output compared with young healthy individuals. Based on these observations, we hypothesize that reductions in the concentrations of cytoplasmic adenine nucleotide, creatine, and phosphate pools that occur with aging impair the myocardial capacity to synthesize ATP at physiological free energy levels and that the resulting changes to myocardial energetic status impair the mechanical pumping ability of the heart. The purpose of this study is to test these hypotheses using an age-structured population model for myocardial metabolism in the adult female population and to determine the potential impact of reductions in key myocardial metabolite pools in causing metabolic/energetic and cardiac mechanical dysfunction associated with aging. To test these hypotheses, we developed a population model for myocardial energetics to predict myocardial ATP, ADP, creatine phosphate, creatine, and inorganic phosphate concentrations as functions of cardiac work and age in the adult female population. Model predictions support our hypotheses and are consistent with previous experimental observations. The major findings provide a novel, to our knowledge, theoretical and computational framework for further probing complex relationships between the energetics and performance of the heart with aging.
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http://dx.doi.org/10.1016/j.bpj.2019.06.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990148PMC
December 2019

Assessing the Validity and Utility of the Guyton Model of Arterial Blood Pressure Control.

Authors:
Daniel A Beard

Hypertension 2018 12;72(6):1272-1273

From the Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor.

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http://dx.doi.org/10.1161/HYPERTENSIONAHA.118.11998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309792PMC
December 2018

Modelling the impact of changes in the extracellular environment on the cytosolic free NAD+/NADH ratio during cell culture.

PLoS One 2018 29;13(11):e0207803. Epub 2018 Nov 29.

Department of Applied Mathematics, Liverpool John Moores University, Liverpool, United Kingdom.

Cancer cells depend on glucose metabolism via glycolysis as a primary energy source, despite the presence of oxygen and fully functioning mitochondria, in order to promote growth, proliferation and longevity. Glycolysis relies upon NAD+ to accept electrons in the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) reaction, linking the redox state of the cytosolic NAD+ pool to glycolytic rate. The free cytosolic NAD+/NADH ratio is involved in over 700 oxidoreductive enzymatic reactions and as such, the NAD+/NADH ratio is regarded as a metabolic readout of overall cellular redox state. Many experimental techniques that monitor or measure total NAD+ and NADH are unable to distinguish between protein-bound and unbound forms. Yet total NAD+/NADH measurements yield little information, since it is the free forms of NAD+ and NADH that determine the kinetic and thermodynamic influence of redox potential on glycolytic rate. Indirect estimations of free NAD+/NADH are based on the lactate/pyruvate (L/P) ratio at chemical equilibrium, but these measurements are often undermined by high lability. To elucidate the sensitivity of the free NAD+/NADH ratio to changes in extracellular substrate, an in silico model of hepatocarcinoma glycolysis was constructed and validated against in vitro data. Model simulations reveal that over experimentally relevant concentrations, changes in extracellular glucose and lactate concentration during routine cancer cell culture can lead to significant deviations in the NAD+/NADH ratio. Based on the principles of chemical equilibrium, the model provides a platform from which experimentally challenging situations may be examined, suggesting that extracellular substrates play an important role in cellular redox and bioenergetic homeostasis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0207803PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6264472PMC
April 2019

High salt diet impairs cerebral blood flow regulation via salt-induced angiotensin II suppression.

Microcirculation 2019 04 15;26(3):e12518. Epub 2019 Jan 15.

Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin.

Objectives: This study sought to determine whether salt-induced ANG II suppression contributes to impaired CBF autoregulation.

Methods: Cerebral autoregulation was evaluated with LDF during graded reductions of blood pressure. Autoregulatory responses in rats fed HS (4% NaCl) diet vs LS (0.4% NaCl) diet were analyzed using linear regression analysis, model-free analysis, and a mechanistic theoretical model of blood flow through cerebral arterioles.

Results: Autoregulation was intact in LS-fed animals as MAP was reduced via graded hemorrhage to approximately 50 mm Hg. Short-term (3 days) and chronic (4 weeks) HS diet impaired CBF autoregulation, as evidenced by progressive reductions of laser Doppler flux with arterial pressure reduction. Chronic low dose ANG II infusion (5 mg/kg/min, i.v.) restored CBF autoregulation between the pre-hemorrhage MAP and 50 mm Hg in rats fed short-term HS diet. Mechanistic-based model analysis showed a reduced myogenic response and reduced baseline VSM tone with short-term HS diet, which was restored by ANG II infusion.

Conclusions: Short-term and chronic HS diet lead to impaired autoregulation in the cerebral circulation, with salt-induced ANG II suppression as a major factor in the initiation of impaired CBF regulation.
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http://dx.doi.org/10.1111/micc.12518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6465152PMC
April 2019

Effects of altered pyruvate dehydrogenase activity on contracting skeletal muscle bioenergetics.

Am J Physiol Regul Integr Comp Physiol 2019 01 21;316(1):R76-R86. Epub 2018 Nov 21.

Department of Physiology, Michigan State University , East Lansing, Michigan.

During aerobic exercise (>65% of maximum oxygen consumption), the primary source of acetyl-CoA to fuel oxidative ATP synthesis in muscle is the pyruvate dehydrogenase (PDH) reaction. This study investigated how regulation of PDH activity affects muscle energetics by determining whether activation of PDH with dichloroacetate (DCA) alters the dynamics of the phosphate potential of rat gastrocnemius muscle during contraction. Twitch contractions were induced in vivo over a broad range of intensities to sample submaximal and maximal aerobic workloads. Muscle phosphorus metabolites were measured in vivo before and after DCA treatment by phosphorus nuclear magnetic resonance spectroscopy. At rest, DCA increased PDH activation compared with control (90 ± 12% vs. 23 ± 3%, P < 0.05), with parallel decreases in inorganic phosphate (P) of 17% (1.4 ± 0.2 vs. 1.7 ± 0.1 mM, P < 0.05) and an increase in the free energy of ATP hydrolysis (ΔG) (-66.2 ± 0.3 vs. -65.6 ± 0.2 kJ/mol, P < 0.05). During stimulation DCA increased steady-state phosphocreatine (PCr) and the magnitude of ΔG, with concomitant reduction in P and ADP concentrations. These effects were not due to kinetic alterations in PCr hydrolysis, resynthesis, or glycolytic ATP production and altered the flow-force relationship between mitochondrial ATP synthesis rate and ΔG. DCA had no significant effect at 1.0- to 2.0-Hz stimulation because physiological mechanisms at these high stimulation levels cause maximal activation of PDH. These data support a role of PDH activation in the regulation of the energetic steady state by altering the phosphate potential (ΔG) at rest and during contraction.
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http://dx.doi.org/10.1152/ajpregu.00321.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6383493PMC
January 2019

Computational model-based assessment of baroreflex function from response to Valsalva maneuver.

J Appl Physiol (1985) 2018 12 20;125(6):1944-1967. Epub 2018 Sep 20.

Molecular and Integrative Physiology, University of Michigan , Ann Arbor, Michigan.

Functional metrics of autonomic control of heart rate, including baroreflex sensitivity, have been shown to be strongly associated with cardiovascular risk. A decrease in baroreflex sensitivity with aging is hypothesized to represent a contributing causal factor in the etiology of primary hypertension. To assess baroreflex function in human subjects, two complementary methods to simulate the response in heart rate elicited by the Valsalva maneuver were developed and applied to data obtained from a cohort of healthy normal volunteers. The first method is based on representing the baroreflex arc as a simple linear filter, transforming changes in arterial pressure to changes in R-R interval. The second method invokes a physiologically based model for arterial mechanics, afferent baroreceptor strain-dependent firing, and control of heart rate via central autonomic response to changes in afferent inputs from aortic and carotid sensors. Analysis based on the linear filter model reveals that the effective response time of the baroreflex arc tends to increase with age in healthy subjects and that the response time/response rate is a predictor of resting systolic pressure. Similar trends were obtained based on the physiologically based model. Analysis of the Valsalva response using the physiologically based model further reveals that different afferent inputs from the carotid sinus and the aortic arch baroreceptors govern different parts of the heart rate response. The observed relationship between baroreflex sensitivity and systolic pressure is surprising because hypertensive subjects were excluded from the study, and there was no observed relationship between arterial pressure and age. NEW & NOTEWORTHY We introduce two methods to assess baroreflex function from data recorded from human subjects performing the Valsalva maneuver. Results demonstrate that the baroreflex response time tends to increase with age in healthy subjects, that response time represents a predictor of resting systolic pressure, and that the Valsalva response reveals different effects mediated by baroreceptors in the carotid sinus compared with those in the aortic arch.
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http://dx.doi.org/10.1152/japplphysiol.00095.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442666PMC
December 2018

Do computers dream of electric glomeruli?

Kidney Int 2018 09;94(3):635

Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA. Electronic address:

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http://dx.doi.org/10.1016/j.kint.2018.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6110099PMC
September 2018

Multiscale Computational Analysis of Right Ventricular Mechanoenergetics.

J Biomech Eng 2018 08;140(8)

Fellow ASME Biomedical Engineering, University of Wisconsin-Madison Medicine, , 1550 Engineering Drive, Madison, WI 53706 e-mail: .

Right ventricular (RV) failure, which occurs in the setting of pressure overload, is characterized by abnormalities in mechanical and energetic function. The effects of these cell- and tissue-level changes on organ-level RV function are unknown. The primary aim of this study was to investigate the effects of myofiber mechanics and mitochondrial energetics on organ-level RV function in the context of pressure overload using a multiscale model of the cardiovascular system. The model integrates the mitochondria-generated metabolite concentrations that drive intracellular actin-myosin cross-bridging and extracellular myocardial tissue mechanics in a biventricular heart model coupled with simple lumped parameter circulations. Three types of pressure overload were simulated and compared to experimental results. The computational model was able to capture a wide range of cardiovascular physiology and pathophysiology from mild RV dysfunction to RV failure. Our results confirm that, in response to pressure overload alone, the RV is able to maintain cardiac output (CO) and predict that alterations in either RV active myofiber mechanics or RV metabolite concentrations are necessary to decrease CO.
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http://dx.doi.org/10.1115/1.4040044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056199PMC
August 2018

Impaired Myofilament Contraction Drives Right Ventricular Failure Secondary to Pressure Overload: Model Simulations, Experimental Validation, and Treatment Predictions.

Front Physiol 2018 27;9:731. Epub 2018 Jun 27.

Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, United States.

Pulmonary hypertension (PH) causes pressure overload leading to right ventricular failure (RVF). Myocardial structure and myocyte mechanics are altered in RVF but the direct impact of these cellular level factors on organ level function remain unclear. A computational model of the cardiovascular system that integrates cellular function into whole organ function has recently been developed. This model is a useful tool for investigating how changes in myocyte structure and mechanics contribute to organ function. We use this model to determine how measured changes in myocyte and myocardial mechanics contribute to RVF at the organ level and predict the impact of myocyte-targeted therapy. A multiscale computational framework was tuned to model PH due to bleomycin exposure in mice. Pressure overload was modeled by increasing the pulmonary vascular resistance (PVR) and decreasing pulmonary artery compliance (CPA). Myocardial fibrosis and the impairment of myocyte maximum force generation (Fmax) were simulated by increasing the collagen content (↑PVR + ↓CPA + fibrosis) and decreasing Fmax (↑PVR + ↓CPA + fibrosis + ↓Fmax). A61603 (A6), a selective α-subtype adrenergic receptor agonist, shown to improve Fmax was simulated to explore targeting myocyte generated Fmax in PH. Increased afterload (RV systolic pressure and arterial elastance) in simulations matched experimental results for bleomycin exposure. Pressure overload alone (↑PVR + ↓CPA) caused decreased RV ejection fraction (EF) similar to experimental findings but preservation of cardiac output (CO). Myocardial fibrosis in the setting of pressure overload (↑PVR + ↓PAC + fibrosis) had minimal impact compared to pressure overload alone. Including impaired myocyte function (↑PVR + ↓PAC + fibrosis + ↓Fmax) reduced CO, similar to experiment, and impaired EF. Simulations predicted that A6 treatment preserves EF and CO despite maintained RV pressure overload. Multiscale computational modeling enabled prediction of the contribution of cellular level changes to whole organ function. Impaired Fmax is a key feature that directly contributes to RVF. Simulations further demonstrate the therapeutic benefit of targeting Fmax, which warrants additional study. Future work should incorporate growth and remodeling into the computational model to enable prediction of the multiscale drivers of the transition from dysfunction to failure.
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http://dx.doi.org/10.3389/fphys.2018.00731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6030352PMC
June 2018

Region-Based Convolutional Neural Nets for Localization of Glomeruli in Trichrome-Stained Whole Kidney Sections.

J Am Soc Nephrol 2018 08 19;29(8):2081-2088. Epub 2018 Jun 19.

Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin;

Histologic examination of fixed renal tissue is widely used to assess morphology and the progression of disease. Commonly reported metrics include glomerular number and injury. However, characterization of renal histology is a time-consuming and user-dependent process. To accelerate and improve the process, we have developed a glomerular localization pipeline for trichrome-stained kidney sections using a machine learning image classification algorithm. We prepared 4-m slices of kidneys from rats of various genetic backgrounds that were subjected to different experimental protocols and mounted the slices on glass slides. All sections used in this analysis were trichrome stained and imaged in bright field at a minimum resolution of 0.92 m per pixel. The training and test datasets for the algorithm comprised 74 and 13 whole renal sections, respectively, totaling over 28,000 glomeruli manually localized. Additionally, because this localizer will be ultimately used for automated assessment of glomerular injury, we assessed bias of the localizer for preferentially identifying healthy or damaged glomeruli. Localizer performance achieved an average precision and recall of 96.94% and 96.79%, respectively, on whole kidney sections without evidence of bias for or against glomerular injury or the need for manual preprocessing. This study presents a novel and robust application of convolutional neural nets for the localization of glomeruli in healthy and damaged trichrome-stained whole-renal section mounts and lays the groundwork for automated glomerular injury scoring.
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http://dx.doi.org/10.1681/ASN.2017111210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6065078PMC
August 2018

Systems-level computational modeling demonstrates fuel selection switching in high capacity running and low capacity running rats.

PLoS Comput Biol 2018 02 23;14(2):e1005982. Epub 2018 Feb 23.

Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States of America.

High capacity and low capacity running rats, HCR and LCR respectively, have been bred to represent two extremes of running endurance and have recently demonstrated disparities in fuel usage during transient aerobic exercise. HCR rats can maintain fatty acid (FA) utilization throughout the course of transient aerobic exercise whereas LCR rats rely predominantly on glucose utilization. We hypothesized that the difference between HCR and LCR fuel utilization could be explained by a difference in mitochondrial density. To test this hypothesis and to investigate mechanisms of fuel selection, we used a constraint-based kinetic analysis of whole-body metabolism to analyze transient exercise data from these rats. Our model analysis used a thermodynamically constrained kinetic framework that accounts for glycolysis, the TCA cycle, and mitochondrial FA transport and oxidation. The model can effectively match the observed relative rates of oxidation of glucose versus FA, as a function of ATP demand. In searching for the minimal differences required to explain metabolic function in HCR versus LCR rats, it was determined that the whole-body metabolic phenotype of LCR, compared to the HCR, could be explained by a ~50% reduction in total mitochondrial activity with an additional 5-fold reduction in mitochondrial FA transport activity. Finally, we postulate that over sustained periods of exercise that LCR can partly overcome the initial deficit in FA catabolic activity by upregulating FA transport and/or oxidation processes.
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http://dx.doi.org/10.1371/journal.pcbi.1005982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841818PMC
February 2018

Human Cardiac P-MR Spectroscopy at 3 Tesla Cannot Detect Failing Myocardial Energy Homeostasis during Exercise.

Front Physiol 2017 27;8:939. Epub 2017 Nov 27.

Department of Radiology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.

Phosphorus-31 magnetic resonance spectroscopy (P-MRS) is a unique non-invasive imaging modality for probing high-energy phosphate metabolism in the human heart. We investigated whether current P-MRS methodology would allow for clinical applications to detect exercise-induced changes in (patho-)physiological myocardial energy metabolism. Hereto, measurement variability and repeatability of three commonly used localized P-MRS methods [3D image-selected spectroscopy (ISIS) and 1D ISIS with 1D chemical shift imaging (CSI) oriented either perpendicular or parallel to the surface coil] to quantify the myocardial phosphocreatine (PCr) to adenosine triphosphate (ATP) ratio in healthy humans ( = 8) at rest were determined on a clinical 3 Tesla MR system. Numerical simulations of myocardial energy homeostasis in response to increased cardiac work rates were performed using a biophysical model of myocardial oxidative metabolism. Hypertrophic cardiomyopathy was modeled by either inefficient sarcomere ATP utilization or decreased mitochondrial ATP synthesis. The effect of creatine depletion on myocardial energy homeostasis was explored for both conditions. The mean myocardial PCr/ATP ratio measured with 3D ISIS was 1.57 ± 0.17 with a large repeatability coefficient of 40.4%. For 1D CSI in a 1D ISIS-selected slice perpendicular to the surface coil, the PCr/ATP ratio was 2.78 ± 0.50 (repeatability 42.5%). With 1D CSI in a 1D ISIS-selected slice parallel to the surface coil, the PCr/ATP ratio was 1.70 ± 0.56 (repeatability 43.7%). The model predicted a PCr/ATP ratio reduction of only 10% at the maximal cardiac work rate in normal myocardium. Hypertrophic cardiomyopathy led to lower PCr/ATP ratios for high cardiac work rates, which was exacerbated by creatine depletion. Simulations illustrated that when conducting cardiac P-MRS exercise stress testing with large measurement error margins, results obtained under pathophysiologic conditions may still lie well within the 95% confidence interval of normal myocardial PCr/ATP dynamics. Current measurement precision of localized P-MRS for quantification of the myocardial PCr/ATP ratio precludes the detection of the changes predicted by computational modeling. This hampers clinical employment of P-MRS for diagnostic testing and risk stratification, and warrants developments in cardiac P-MRS exercise stress testing methodology.
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http://dx.doi.org/10.3389/fphys.2017.00939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5712006PMC
November 2017

Crops : Generating Virtual Crops Using an Integrative and Multi-scale Modeling Platform.

Front Plant Sci 2017 15;8:786. Epub 2017 May 15.

CAS Key Laboratory for Computational Biology-State Key Laboratory for Hybrid Rice, Partner Institute for Computational Biology, Chinese Academy of SciencesShanghai, China.

Multi-scale models can facilitate whole plant simulations by linking gene networks, protein synthesis, metabolic pathways, physiology, and growth. Whole plant models can be further integrated with ecosystem, weather, and climate models to predict how various interactions respond to environmental perturbations. These models have the potential to fill in missing mechanistic details and generate new hypotheses to prioritize directed engineering efforts. Outcomes will potentially accelerate improvement of crop yield, sustainability, and increase future food security. It is time for a paradigm shift in plant modeling, from largely isolated efforts to a connected community that takes advantage of advances in high performance computing and mechanistic understanding of plant processes. Tools for guiding future crop breeding and engineering, understanding the implications of discoveries at the molecular level for whole plant behavior, and improved prediction of plant and ecosystem responses to the environment are urgently needed. The purpose of this perspective is to introduce Crops (cropsinsilico.org), an integrative and multi-scale modeling platform, as one solution that combines isolated modeling efforts toward the generation of virtual crops, which is open and accessible to the entire plant biology community. The major challenges involved both in the development and deployment of a shared, multi-scale modeling platform, which are summarized in this prospectus, were recently identified during the first Crops Symposium and Workshop.
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http://dx.doi.org/10.3389/fpls.2017.00786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5430029PMC
May 2017

Tautological Nature of Guyton's Theory of Blood Pressure Control.

Authors:
Daniel A Beard

Am J Hypertens 2017 07;30(7):e5

Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.

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http://dx.doi.org/10.1093/ajh/hpx038DOI Listing
July 2017

The feasibility of genome-scale biological network inference using Graphics Processing Units.

Algorithms Mol Biol 2017 20;12. Epub 2017 Mar 20.

Department of Molecular and Integrative Physiology, University of Michigan, North Campus Research Complex, Ann Arbor, MI USA.

Systems research spanning fields from biology to finance involves the identification of models to represent the underpinnings of complex systems. Formal approaches for data-driven identification of network interactions include statistical inference-based approaches and methods to identify dynamical systems models that are capable of fitting multivariate data. Availability of large data sets and so-called 'big data' applications in biology present great opportunities as well as major challenges for systems identification/reverse engineering applications. For example, both inverse identification and forward simulations of genome-scale gene regulatory network models pose compute-intensive problems. This issue is addressed here by combining the processing power of Graphics Processing Units (GPUs) and a parallel reverse engineering algorithm for inference of regulatory networks. It is shown that, given an appropriate data set, information on genome-scale networks (systems of 1000 or more state variables) can be inferred using a reverse-engineering algorithm in a matter of days on a small-scale modern GPU cluster.
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http://dx.doi.org/10.1186/s13015-017-0100-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5360040PMC
March 2017

Estrogen maintains mitochondrial content and function in the right ventricle of rats with pulmonary hypertension.

Physiol Rep 2017 Mar;5(6)

Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, Wisconsin

The typical cause of death in pulmonary hypertension (PH) is right ventricular (RV) failure, with females showing better survival rates than males. Recently, metabolic shift and mitochondrial dysfunction have been demonstrated in RV failure secondary to PH In light of evidence showing that estrogen protects mitochondrial function and biogenesis in noncardiovascular systems, we hypothesized that the mechanism by which estrogen preserves RV function is via protection of mitochondrial content and oxidative capacity in PH We used a well-established model of PH (Sugen+Hypoxia) in ovariectomized female rats with/without estrogen treatment. RV functional measures were derived from pressure-volume relationships measured via RV catheterization in live rats. Citrate synthase activity, a marker of mitochondrial density, was measured in both RV and LV tissues. Respiratory capacity of mitochondria isolated from RV was measured using oxygraphy. We found that RV ventricular-vascular coupling efficiency decreased in the placebo-treated SuHx rats (0.78 ± 0.10 vs. 1.50 ± 0.13 in control,  < 0.05), whereas estrogen restored it. Mitochondrial density decreased in placebo-treated SuHx rats (0.12 ± 0.01 vs. 0.15 ± 0.01 U citrate synthase/mg in control,  < 0.05), and estrogen attenuated the decrease. Mitochondrial quality and oxidative capacity tended to be lower in placebo-treated SuHx rats only. The changes in mitochondrial biogenesis and function paralleled the expression levels of PGC-1 in RV Our results suggest that estrogen protects RV function by preserving mitochondrial content and oxidative capacity. This provides a mechanism by which estrogen provides protection in female PH patients and paves the way to develop estrogen and its targets as a novel RV-specific therapy for PH.
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http://dx.doi.org/10.14814/phy2.13157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5371553PMC
March 2017

Influence of metabolic dysfunction on cardiac mechanics in decompensated hypertrophy and heart failure.

J Mol Cell Cardiol 2016 05 13;94:162-175. Epub 2016 Apr 13.

Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, United States. Electronic address:

Alterations in energetic state of the myocardium are associated with decompensated heart failure in humans and in animal models. However, the functional consequences of the observed changes in energetic state on mechanical function are not known. The primary aim of the study was to quantify mechanical/energetic coupling in the heart and to determine if energetic dysfunction can contribute to mechanical failure. A secondary aim was to apply a quantitative systems pharmacology analysis to investigate the effects of drugs that target cross-bridge cycling kinetics in heart failure-associated energetic dysfunction. Herein, a model of metabolite- and calcium-dependent myocardial mechanics was developed from calcium concentration and tension time courses in rat cardiac muscle obtained at different lengths and stimulation frequencies. The muscle dynamics model accounting for the effect of metabolites was integrated into a model of the cardiac ventricles to simulate pressure-volume dynamics in the heart. This cardiac model was integrated into a simple model of the circulation to investigate the effects of metabolic state on whole-body function. Simulations predict that reductions in metabolite pools observed in canine models of heart failure can cause systolic dysfunction, blood volume expansion, venous congestion, and ventricular dilation. Simulations also predict that myosin-activating drugs may partially counteract the effects of energetic state on cross-bridge mechanics in heart failure while increasing myocardial oxygen consumption. Our model analysis demonstrates how metabolic changes observed in heart failure are alone sufficient to cause systolic dysfunction and whole-body heart failure symptoms.
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http://dx.doi.org/10.1016/j.yjmcc.2016.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5505661PMC
May 2016

Mitochondrial structure and function are not different between nonfailing donor and end-stage failing human hearts.

FASEB J 2016 08 13;30(8):2698-707. Epub 2016 Apr 13.

Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, Missouri, USA; George Washington University, Washington, D.C., USA

During human heart failure, the balance of cardiac energy use switches from predominantly fatty acids (FAs) to glucose. We hypothesized that this substrate shift was the result of mitochondrial degeneration; therefore, we examined mitochondrial oxidation and ultrastructure in the failing human heart by using respirometry, transmission electron microscopy, and gene expression studies of demographically matched donor and failing human heart left ventricular (LV) tissues. Surprisingly, respiratory capacities for failing LV isolated mitochondria (n = 9) were not significantly diminished compared with donor LV isolated mitochondria (n = 7) for glycolysis (pyruvate + malate)- or FA (palmitoylcarnitine)-derived substrates, and mitochondrial densities, assessed via citrate synthase activity, were consistent between groups. Transmission electron microscopy images also showed no ultrastructural remodeling for failing vs. donor mitochondria; however, the fraction of lipid droplets (LDs) in direct contact with a mitochondrion was reduced, and the average distance between an LD and its nearest neighboring mitochondrion was increased. Analysis of FA processing gene expression between donor and failing LVs revealed 0.64-fold reduced transcript levels for the mitochondrial-LD tether, perilipin 5, in the failing myocardium (P = 0.003). Thus, reduced FA use in heart failure may result from improper delivery, potentially via decreased perilipin 5 expression and mitochondrial-LD tethering, and not from intrinsic mitochondrial dysfunction.-Holzem, K. M., Vinnakota, K. C., Ravikumar, V. K., Madden, E. J., Ewald, G. A., Dikranian, K., Beard, D. A., Efimov, I. R. Mitochondrial structure and function are not different between nonfailing donor and end-stage failing human hearts.
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http://dx.doi.org/10.1096/fj.201500118RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4970604PMC
August 2016

Improving the physiological realism of experimental models.

Interface Focus 2016 Apr;6(2):20150076

Neuroimaging Centre, Division of Neuroscience, University Medical Center Groningen, Groningen, The Netherlands; Department of Radiology, Academic Medical Center Amsterdam, University of Amsterdam, Amsterdam, The Netherlands.

The Virtual Physiological Human (VPH) project aims to develop integrative, explanatory and predictive computational models (C-Models) as numerical investigational tools to study disease, identify and design effective therapies and provide an in silico platform for drug screening. Ultimately, these models rely on the analysis and integration of experimental data. As such, the success of VPH depends on the availability of physiologically realistic experimental models (E-Models) of human organ function that can be parametrized to test the numerical models. Here, the current state of suitable E-models, ranging from in vitro non-human cell organelles to in vivo human organ systems, is discussed. Specifically, challenges and recent progress in improving the physiological realism of E-models that may benefit the VPH project are highlighted and discussed using examples from the field of research on cardiovascular disease, musculoskeletal disorders, diabetes and Parkinson's disease.
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http://dx.doi.org/10.1098/rsfs.2015.0076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4759746PMC
April 2016

Open-loop (feed-forward) and feedback control of coronary blood flow during exercise, cardiac pacing, and pressure changes.

Am J Physiol Heart Circ Physiol 2016 06 1;310(11):H1683-94. Epub 2016 Apr 1.

Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan; and

A control system model was developed to analyze data on in vivo coronary blood flow regulation and to probe how different mechanisms work together to control coronary flow from rest to exercise, and under a variety of experimental conditions, including cardiac pacing and with changes in coronary arterial pressure (autoregulation). In the model coronary flow is determined by the combined action of a feedback pathway signal that is determined by the level of plasma ATP in coronary venous blood, an adrenergic open-loop (feed-forward) signal that increases with exercise, and a contribution of pressure-mediated myogenic control. The model was identified based on data from exercise experiments where myocardial oxygen extraction, coronary flow, cardiac interstitial norepinephrine concentration, and arterial and coronary venous plasma ATP concentrations were measured during control and during adrenergic and purinergic receptor blockade conditions. The identified model was used to quantify the relative contributions of open-loop and feedback pathways and to illustrate the degree of redundancy in the control of coronary flow. The results indicate that the adrenergic open-loop control component is responsible for most of the increase in coronary blood flow that occurs during high levels of exercise. However, the adenine nucleotide-mediated metabolic feedback control component is essential. The model was evaluated by predicting coronary flow in cardiac pacing and autoregulation experiments with reasonable fits to the data. The analysis shows that a model in which coronary venous plasma adenine nucleotides are a signal in local metabolic feedback control of coronary flow is consistent with the available data.
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http://dx.doi.org/10.1152/ajpheart.00663.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4935508PMC
June 2016

Feedback Regulation and Time Hierarchy of Oxidative Phosphorylation in Cardiac Mitochondria.

Biophys J 2016 Feb;110(4):972-80

Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan.

To determine how oxidative ATP synthesis is regulated in the heart, the responses of cardiac mitochondria oxidizing pyruvate to alterations in [ATP], [ADP], and inorganic phosphate ([Pi]) were characterized over a range of steady-state levels of extramitochondrial [ATP], [ADP], and [Pi]. Evolution of the steady states of the measured variables with the flux of respiration shows that: (1) a higher phosphorylation potential is achieved by mitochondria at higher [Pi] for a given flux of respiration; (2) the time hierarchy of oxidative phosphorylation is given by phosphorylation subsystem, electron transport chain, and substrate dehydrogenation subsystems listed in increasing order of their response times; (3) the matrix ATP hydrolysis mass action ratio [ADP] × [Pi]/[ATP] provides feedback to the substrate dehydrogenation flux over the entire range of respiratory flux examined in this study; and finally, (4) contrary to previous models of regulation of oxidative phosphorylation, [Pi] does not modulate the activity of complex III.
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http://dx.doi.org/10.1016/j.bpj.2016.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4776028PMC
February 2016

Catalytic Coupling of Oxidative Phosphorylation, ATP Demand, and Reactive Oxygen Species Generation.

Biophys J 2016 Feb;110(4):962-71

Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan.

Competing models of mitochondrial energy metabolism in the heart are highly disputed. In addition, the mechanisms of reactive oxygen species (ROS) production and scavenging are not well understood. To deepen our understanding of these processes, a computer model was developed to integrate the biophysical processes of oxidative phosphorylation and ROS generation. The model was calibrated with experimental data obtained from isolated rat heart mitochondria subjected to physiological conditions and workloads. Model simulations show that changes in the quinone pool redox state are responsible for the apparent inorganic phosphate activation of complex III. Model simulations predict that complex III is responsible for more ROS production during physiological working conditions relative to complex I. However, this relationship is reversed under pathological conditions. Finally, model analysis reveals how a highly reduced quinone pool caused by elevated levels of succinate is likely responsible for the burst of ROS seen during reperfusion after ischemia.
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http://dx.doi.org/10.1016/j.bpj.2015.09.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4776027PMC
February 2016
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