Ranjan K Dash

Medical College of Wisconsin | MCW · Department of Biomedical Engineering

Quantitative measurement of the degree of hepatic ischemia-reperfusion injury (IRI) is crucial for developing therapeutic strategies for its treatment. We hypothesized that clearance of fluorescent dye through bile metabolism may reflect the degree of hepatic IRI. In this study, we investigated sodium fluorescein clearance kinetics in blood and bil...

Rationale: The kinetics and efficiency of mitochondrial oxidative phosphorylation (OxPhos) is determined by the availability and utilization of particular respiratory substrates. Although the heart and kidney represent the two major energy consuming organs in the body, the substrate dependency of their mitochondrial OxPhos has not been characteriz...

Rationale: Reactive oxygen species (ROS; e.g. O2 · - and H2 O2 ) play important roles in both physiological and pathophysiological processes. ROS in low concentrations contribute to physiological processes, such as cellular redox signaling and phagocytosis, whereas ROS in high concentrations are toxic to the cell causing tissue injury contributing...

Rationale: Kidney nephrons actively reabsorb 99% of the filtrate to maintain body fluid and solute homeostasis. A large amount of ATP synthesis and O2 consumption must work coordinal to support this demand. We hypothesized that mitochondrial function of proximal tubules (PT) and medullary thick ascending limbs (mTAL) is altered during the developm...

The metabolism of oxygen and substrates in the kidney under normal conditions and in salt-sensitive hypertension is still not well understood. A novel method was developed to collect renal arteriovenous blood and urine from conscious freely moving rats, while measuring renal blood flow (RBF) and blood pressure (BP). As such, global renal O2 consump...

Rationale: It is recognized that the kinetics and efficiency of mitochondrial O2 consumption for ATP production depend on the choice of respiratory substrates. Various substrates differentially generate the reducing equivalents NADH and FADH2 via the tricarboxylic acid (TCA) cycle that feed electrons to the electron transport chain (ETC) driving o...

Objective: Dissipation of mitochondrial membrane potential (Δψm ) is a hallmark of mitochondrial dysfunction, which plays a key in the pathogenesis of Acute Respiratory Distress Syndrome (ARDS). Our objective was to use a previously developed experimental-computational approach to estimate tissue Δψm in isolated perfused lungs of rats exposed to h...

Rationale: Salt-sensitive hypertension is globally widespread and associated with increased risk of cardiovascular eventsand kidney disease. Although excess dietary salt intake is a major cause of these damaging effects, many of the underlying mechanisms remain poorly defined. Specifically, it is not understood how the critical energy needs of the...

Mitochondrial dehydrogenases are differentially stimulated by Ca2+. Ca2+ has also diverse regulatory effects on mitochondrial transporters and other enzymes. However, the consequences of these regulatory effects on mitochondrial oxidative phosphorylation (OxPhos) and ATP production, and the dependencies of these consequences on respiratory substrat...

Dissipation of mitochondrial membrane potential (Δψ m ) is a hallmark of mitochondrial dysfunction. our objective was to use a previously developed experimental-computational approach to estimate tissue Δψ m in intact lungs of rats exposed to hyperoxia, and to evaluate the ability of duroquinone (DQ) to reverse any hyperoxia-induced depolarization...

Different cancer cell lines can have varying responses to the same perturbations or stressful conditions. Cancer cells that have DNA damage checkpoint-related mutations are often more sensitive to gene perturbations including altered Plk1 and p53 activities than cancer cells without these mutations. The perturbations often induce a cell cycle arres...

The kinetics and efficiency of mitochondrial oxidative phosphorylation (OxPhos) can depend on the choice of respiratory substrates. Furthermore, potential differences in this substrate dependency among different tissues are not well-understood. Here, we determined the effects of different substrates on the kinetics and efficiency of OxPhos in isola...

It has appeared evident that blood flow to the renal cortex which is required for glomerular filtration far exceeds the delivery of O 2 required for tubular metabolic needs. Yet, the metabolic needs of kidneys are second only to the heart per gram tissue and changes in O 2 extraction and utilization have not been directly measured in face of enhanc...

Introduction: Doxorubicin-Induced Cardiotoxicity (DIC) is one of the most common clinical complications in cancer patients. Patients with diabetes have a higher incidence of breast cancer, and their risks of developing DIC is also higher as compared to healthy patients. The human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) hav...

Reactive oxygen species (ROS) play a crucial role in many physiological processes. However, ROS overproduction leads to oxidative stress, which plays a critical role in cell injury/death and the pathogenesis of many diseases. Members of NADPH oxidase (NOX) family, most of which are comprised of membrane and cytosolic components, are known to be the...

Hypertension is a complex disease and a leading cause of morbidity and mortality globally. Although oxidative stress and mitochondrial dysfunction have been found in the kidney in various models of hypertension, progressive alteration of mitochondrial oxidative phosphorylation (OxPhos) in the kidney during the development of salt-sensitive hyperten...

The cellular protein-protein interaction network that governs cellular proliferation (cell cycle) is highly complex. Here, we have developed a novel computational model of human mitotic cell cycle, integrating diverse cellular mechanisms, for the purpose of generating new hypotheses and predicting new experiments designed to help understand complex...

The second gas effect occurs when high inspired concentrations of a first gas, usually nitrous oxide, enhance the uptake of other gases administered simultaneously. The second gas effect is greater in blood than in the gas phase; persists well into the period of nitrous oxide maintenance anesthesia; increases as the degree of ventilation-perfusion...

Mitochondrial membrane potential (ΔΨ m ) plays a key role in vital mitochondrial functions, and its dissipation is a hallmark of mitochondrial dysfunction. The objective of this study was to develop an experimental and computational approach for estimating ΔΨ m in intact rat lungs using the lipophilic fluorescent cationic dye rhodamine 6G (R6G). Ra...

We present a new size-modified Poisson-Boltzmann ion channel (SMPBIC) model and use it to calculate the electrostatic potential, ionic concentrations, and electrostatic solvation free energy for a voltage-dependent anion channel (VDAC) on a biological membrane in a solution mixture of multiple ionic species. In particular, the new SMPBIC model adop...

Calcium ion concentration modulates the function of several mitochondrial enzymes. Specifically, the kinetic operations of the decarboxylating dehydrogenases pyruvate dehydrogenase, isocitrate dehydrogenase, α-ketoglutarate dehydrogenase are all affected by [Ca2+]. Previous studies have shown that, despite its ability to affect the function of spec...

Hyperglycemia is a critical factor in the development of endothelial dysfunction in type 2 diabetes mellitus (T2DM). Whether hyperglycemic states result in a disruption of similar molecular mechanisms in endothelial cells under both diabetic and non-diabetic states, remains largely unknown. This study aimed to address this gap in knowledge through...

Altered lung tissue bioenergetics plays a key role in the pathogenesis of lung diseases. A wealth of information exists regarding the bioenergetic processes in mitochondria isolated from rat lungs, cultured pulmonary endothelial cells, and intact rat lungs under physiological and pathophysiological conditions. However, the interdependence of those...

Mitochondrial (m) Ca²⁺ influx is largely dependent on membrane potential (ΔΨm), whereas mCa²⁺ efflux occurs primarily via Ca²⁺ ion exchangers. We probed the kinetics of Ca²⁺/H⁺ exchange (CHEm) in guinea pig cardiac muscle mitochondria. We tested if net mCa²⁺ flux is altered during a matrix inward H⁺ leak that is dependent on matrix H⁺ pumping by AT...

Reactive oxygen species (ROS) play an important role in cell signaling, growth, and immunity. However, when produced in excess, they are toxic to the cell and lead to premature aging and a myriad of pathologies, including cardiovascular and renal diseases. A major source of ROS in many cells is the family of NADPH oxidase (NOX), comprising of membr...

Cardiovascular-related pathologies are the single leading cause of death in patients with chronic kidney disease (CKD). Previously, we found that a 5/6th nephrectomy model of CKD leads to an upregulation of miR-21-5p in the left ventricle, targeting peroxisome proliferator-activated receptor-α and altering the expression of numerous transcripts inv...

The second gas effect (SGE) occurs when nitrous oxide enhances the uptake of volatile anesthetics administered simultaneously. Recent work shows that the SGE is greater in blood than in the gas phase, that this is due to ventilation-perfusion mismatch, that as mismatch increases, the SGE increases in blood but is diminished in the gas phase, and th...

The objectives of this study were to develop a robust protocol for measuring the rate of hydrogen peroxide (H2O2) production in isolated perfused rat lungs, as an index of oxidative stress, and to determine cellular sources of the measured H2O2 using the extracellular probe Amplex red (AR). AR was added to recirculating perfusate in an isolated per...

Integrated computational modeling provides a mechanistic and quantitative framework for describing lung mitochondrial bioenergetics. Thus, the objective of this study was to develop and validate a thermodynamically-constrained integrated computational model of the bioenergetics of isolated lung mitochondria. The model incorporates the major biochem...

Reactions and transport processes included in the integrated bioenergetics model along with model governing mass balance equations. This file consists of four parts. Part A lists the reaction and transport processes in the mitochondrial bioenergetics model. Part B provides a description of the derivation of the generalized metabolic reaction and tr...

Background: Recent clinical studies suggest that the magnitude of the second gas effect is considerably greater on arterial blood partial pressures of volatile agents than on end-expired partial pressures, and a significant second gas effect on blood partial pressures of oxygen and volatile agents occurs even at relatively low rates of nitrous oxi...

Cytochrome c oxidase (CcO) catalyzes the exothermic reduction of O2 to H2O by utilizing electrons from cytochrome c, and hence plays a crucial role in ATP production. Although details on the enzyme structure and redox centers involved in O2 reduction have been known, there still remains a considerable ambiguity on its mechanism of action, e.g. the...

Oxidation of substrates to generate ATP in mitochondria is mediated by redox reactions of NADH and FADH2. Cardiac ischemia and reperfusion (IR) injury compromises mitochondrial oxidative phosphorylation. We hypothesize that IR alters the metabolic heterogeneity of mitochondrial redox state of the heart that is only evident in the 3-D optical cryoim...

The manner in which mitochondria take up and store Ca2+ remains highly debated. Recent experimental and computational evidence has suggested the presence of at least two modes of Ca2+ uptake and a complex Ca2+ sequestration mechanism in mitochondria. But how Mg2+ regulates these different modes of Ca2+ uptake as well as mitochondrial Ca2+ sequestra...

The ‘Pathway for Oxygen’ is captured in a set of models describing quantitative relationships between fluxes and driving forces for the flux of oxygen from the external air source to the mitochondrial sink at cytochrome oxidase. The intervening processes involve convection, membrane permeation, diffusion of free and heme-bound O2 and enzymatic reac...

Equations for blood oxyhemoglobin (HbO2) and carbaminohemoglobin (HbCO2) dissociation curves that incorporate nonlinear biochemical interactions of oxygen and carbon dioxide with hemoglobin (Hb), covering a wide range of physiological conditions, are crucial for a number of practical applications. These include the development of physiologically-ba...

The goal of this study was to quantify and correlate the contribution of the cytosolic p67phox subunit of NADPH-oxidase2 (Nox2) to mitochondrial oxidative stress in the kidneys of the Dahl salt-sensitive (SS) hypertensive rat. Whole kidney redox states were uniquely assessed using a custom designed optical fluorescence 3D cryoimager to acquire mult...

NADH:ubiquinone oxidoreductase (complex I) is a proton pump in the electron transport chain that can produce a significant amounts of superoxide and hydrogen peroxide. While the flavin mononucleotide (FMN) is the putative site for hydrogen peroxide generation, sites responsible for superoxide are less certain. Here, data on complex I kinetics and R...

The voltage-dependent anion channel (VDAC) is the main conduit for permeation of solutes (including nucleotides and metabolites) of up to 5 kDa across the mitochondrial outer membrane (MOM). Recent studies suggest that VDAC activity is regulated via post-translational modifications (PTMs). Yet the nature and effect of these modifications is not und...

NADH:ubiquinone oxidoreductase (Complex I) is a proton pump in the electron transport chain that can produce a significant amounts of superoxide and hydrogen peroxide. While the flavin mononucleotide (FMN) is the putative site for hydrogen peroxide generation, sites responsible for superoxide are less certain. Here, data on Complex I kinetics and R...

The thioredoxin system, which consists of a family of proteins, including thioredoxin (Trx), peroxiredoxin (Prx), and thioredoxin reductase (TrxR), plays a critical role in the defense against oxidative stress by removing harmful hydrogen peroxide (H2O2). Specifically, Trx donates electrons to Prx to remove H2O2 and then TrxR maintains the reduced...

Mitochondria are critical modulators of cell function and are increasingly recognized as proximal sensors and effectors that ultimately determine the balance between cell survival and cell death. Volatile anesthetics (VA) are long known for their cardioprotective effects, as demonstrated by improved mitochondrial and cellular functions, and by redu...

Cardiac mitochondria can act as a significant Ca(2+) sink and shape cytosolic Ca(2+) signals affecting various cellular processes, such as energy metabolism and excitation-contraction coupling. However, different mitochondrial Ca(2+) uptake mechanisms are still not well understood. In this study, we analyzed recently published Ca(2+) uptake experim...