scholarly journals ATP-consuming futile cycles as energy dissipating mechanisms to counteract obesity

2021 ◽  
Author(s):  
Alexandra J. Brownstein ◽  
Michaela Veliova ◽  
Rebeca Acin-Perez ◽  
Marc Liesa ◽  
Orian S. Shirihai
Keyword(s):  
Energy Dissipation ◽  
Energy Homeostasis ◽  
Atp Synthesis ◽  
Heat Energy ◽  
Mitochondrial Uncoupling ◽  
Energy Consuming ◽  
Futile Cycles ◽  
Import And Export ◽  
Metabolic Reactions ◽  
Oxidative Function

AbstractObesity results from an imbalance in energy homeostasis, whereby excessive energy intake exceeds caloric expenditure. Energy can be dissipated out of an organism by producing heat (thermogenesis), explaining the long-standing interest in exploiting thermogenic processes to counteract obesity. Mitochondrial uncoupling is a process that expends energy by oxidizing nutrients to produce heat, instead of ATP synthesis. Energy can also be dissipated through mechanisms that do not involve mitochondrial uncoupling. Such mechanisms include futile cycles described as metabolic reactions that consume ATP to produce a product from a substrate but then converting the product back into the original substrate, releasing the energy as heat. Energy dissipation driven by cellular ATP demand can be regulated by adjusting the speed and number of futile cycles. Energy consuming futile cycles that are reviewed here are lipolysis/fatty acid re-esterification cycle, creatine/phosphocreatine cycle, and the SERCA-mediated calcium import and export cycle. Their reliance on ATP emphasizes that mitochondrial oxidative function coupled to ATP synthesis, and not just uncoupling, can play a role in thermogenic energy dissipation. Here, we review ATP consuming futile cycles, the evidence for their function in humans, and their potential employment as a strategy to dissipate energy and counteract obesity.

AMP kinase (PRKAA1)

2014 ◽  
Vol 67 (9) ◽  
pp. 758-763 ◽  
Author(s):  
Sukriti Krishan ◽  
Des R Richardson ◽  
Sumit Sahni
Keyword(s):  
Energy Homeostasis ◽  
Atp Synthesis ◽  
Cellular Growth ◽  
Α Subunit ◽  
Cellular Energy ◽  
Therapeutic Drugs ◽  
Energy Sensor ◽  
Energy Consuming ◽  
Cardiac Disorders ◽  
Amp Activated Protein Kinase

The PRKAA1 gene encodes the catalytic α-subunit of 5′ AMP-activated protein kinase (AMPK). AMPK is a cellular energy sensor that maintains energy homeostasis within the cell and is activated when the AMP/ATP ratio increases. When activated, AMPK increases catabolic processes that increase ATP synthesis and inhibit anabolic processes that require ATP. Additionally, AMPK also plays a role in activating autophagy and inhibiting energy consuming processes, such as cellular growth and proliferation. Due to its role in energy metabolism, it could act as a potential target of many therapeutic drugs that could be useful in the treatment of several diseases, for example, diabetes. Moreover, AMPK has been shown to be involved in inhibiting tumour growth and metastasis, and has also been implicated in the pathology of neurodegenerative and cardiac disorders. Hence, a better understanding of AMPK and its role in various pathological conditions could enable the development of strategies to use it as a therapeutic target.

scholarly journals Bioenergetic characterization of mouse podocytes

2010 ◽  
Vol 299 (2) ◽  
pp. C464-C476 ◽  
Author(s):  
Yoshifusa Abe ◽  
Toru Sakairi ◽  
Hiroshi Kajiyama ◽  
Shashi Shrivastav ◽  
Craig Beeson ◽  
...  
Keyword(s):  
Oxygen Consumption ◽  
Mitochondrial Respiration ◽  
Energy Homeostasis ◽  
Atp Synthesis ◽  
Cellular Respiration ◽  
Similar Data ◽  
Primary Role ◽  
Atp Content ◽  
Mitochondrial Uncoupling ◽  
Primary Mouse

Mitochondrial dysfunction contributes to podocyte injury, but normal podocyte bioenergetics have not been characterized. We measured oxygen consumption rates (OCR) and extracellular acidification rates (ECAR), using a transformed mouse podocyte cell line and the Seahorse Bioscience XF24 Extracellular Flux Analyzer. Basal OCR and ECAR were 55.2 ± 9.9 pmol/min and 3.1 ± 1.9 milli-pH units/min, respectively. The complex V inhibitor oligomycin reduced OCR to ∼45% of baseline rates, indicating that ∼55% of cellular oxygen consumption was coupled to ATP synthesis. Rotenone, a complex I inhibitor, reduced OCR to ∼25% of the baseline rates, suggesting that mitochondrial respiration accounted for ∼75% of the total cellular respiration. Thus ∼75% of mitochondrial respiration was coupled to ATP synthesis and ∼25% was accounted for by proton leak. Carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP), which uncouples electron transport from ATP generation, increased OCR and ECAR to ∼360% and 840% of control levels. FCCP plus rotenone reduced ATP content by 60%, the glycolysis inhibitor 2-deoxyglucose reduced ATP by 35%, and 2-deoxyglucose in combination with FCCP or rotenone reduced ATP by >85%. The lactate dehydrogenase inhibitor oxamate and 2-deoxyglucose did not reduce ECAR, and 2-deoxyglucose had no effect on OCR, although 2-deoxyglucose reduced ATP content by 25%. Mitochondrial uncoupling induced by FCCP was associated with increased OCR with certain substrates, including lactate, glucose, pyruvate, and palmitate. Replication of these experiments in primary mouse podocytes yielded similar data. We conclude that mitochondria play the primary role in maintaining podocyte energy homeostasis, while glycolysis makes a lesser contribution.

Mitochondrial Inhibition Prior to Oxygen-Withdrawal Facilitates the Occurrence of Hypoxia-Induced Spreading Depression in Rat Hippocampal Slices

2006 ◽  
Vol 96 (1) ◽  
pp. 492-504 ◽  
Author(s):  
Florian J. Gerich ◽  
Sebastian Hepp ◽  
Irmelin Probst ◽  
Michael Müller
Keyword(s):  
Mitochondrial Respiration ◽  
Spreading Depression ◽  
Hippocampal Slices ◽  
Atp Synthesis ◽  
Atp Depletion ◽  
Mitochondrial Uncoupling ◽  
Ca1 Neurons ◽  
Optical Signals ◽  
Nitropropionic Acid ◽  
Carbonyl Cyanide

Oxygen withdrawal blocks mitochondrial respiration. In rat hippocampal slices, this triggers a massive depolarization of CA1 neurons and a negative shift of the extracellular DC potential, the characteristic sign of hypoxia-induced spreading depression (HSD). To unveil the contribution of mitochondria to the sensing of hypoxia and the ignition of HSD, we modified mitochondrial function. Mitochondrial uncoupling by carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP, 1 μM) prior to hypoxia hastened the onset and shortened the duration of HSD. Blocking mitochondrial ATP synthesis by oligomycin (10 μg/ml) was without effect. Inhibition of mitochondrial respiration by rotenone (20 μM), diphenyleneiodonium (25 μM), or antimycin A (20 μM) also hastened HSD onset and shortened HSD duration. 3-nitropropionic acid (1 mM) increased HSD duration. Cyanide (100 μM) hastened HSD onset and increased HSD duration. At higher concentrations, cyanide (1 mM), azide (2 mM), and FCCP (10 μM) triggered SD episodes on their own. Compared with control HSD, the spatial extent of the intrinsic optical signals of cyanide- and azide-induced SDs was more pronounced. Monitoring NADH (nicotinamide adenine dinucleotide) and FAD (flavin adenine dinucleotide) autofluorescence and mitochondrial membrane potential verified the mitochondrial targeting by the drugs used. Except 1 mM cyanide, no treatment reduced cellular ATP levels severely and no correlation was found between ATP, NADH, or FAD levels and the time to HSD onset. Therefore ATP depletion or a cytosolic reducing shift due to NADH/FADH2 accumulation cannot serve as a general explanation for the hastening of HSD onset on mitochondrial inhibition. Additional redox couples (glutathione) or events downstream of the mitochondrial depolarization need to be considered.

scholarly journals Systemic impact of the expression of the mitochondrial alternative oxidase on Drosophila development

2021 ◽  
Author(s):  
André F. Camargo ◽  
Sina Saari ◽  
Geovana S. Garcia ◽  
Marina M. Chioda ◽  
Murilo F. Othonicar ◽  
...  
Keyword(s):  
Metabolic Regulation ◽  
Alternative Oxidase ◽  
Atp Synthesis ◽  
Biomass Accumulation ◽  
Proton Pumping ◽  
Membrane Phospholipids ◽  
Mitochondrial Uncoupling ◽  
Morphological Alterations ◽  
Beneficial Effects ◽  
Tissue Proliferation

Despite the beneficial effects shown when the mitochondrial alternative oxidase AOX from Ciona intestinalis (Tunicata: Ascidiacea) is xenotopically expressed in mammalian and insect models, important detrimental outcomes have also been reported, raising concerns regarding its envisioned deployment as a therapy enzyme for human mitochondrial and related diseases. Because of its non-proton pumping terminal oxidase activity, AOX can bypass the cytochrome c segment of the respiratory chain and alleviate the possible overload of electrons that occurs upon oxidative phosphorylation (OXPHOS) dysfunction, not contributing though to the proton-motive force needed for mitochondrial ATP synthesis. We have shown previously that AOX-expressing flies present a dramatic drop in pupal viability when the larvae are cultured on a low nutrient diet, indicating that AOX interferes with normal developmental metabolism. Here, we applied combined omics analyses to show that the interaction between low nutrient diet and AOX expression causes a general alteration of larval amino acid metabolism and lipid accumulation, which are associated with functional and morphological alterations of the larval digestive tract and with a drastic decrease in larval biomass accumulation. Pupae at the pre-lethality stage present a general downregulation of mitochondrial metabolism and a signature for starvation and deregulated signaling processes. This AOX-induced lethality is partially rescued when the low nutrient diet is supplemented with tryptophan and/or methionine. The developmental dependence on these amino acids, associated with elevated levels of lactate dehydrogenase, lactate, 2-hydroxyglutarate, choline-containing metabolites and breakdown products of membrane phospholipids, indicates that AOX expression promotes tissue proliferation and growth of the Drosophila larvae, but this is ultimately limited by energy dissipation via mitochondrial uncoupling. We speculate that the combination of diet and AOX expression may be used for the metabolic regulation of proliferative tissues, such as tumors.

scholarly journals Why is cyanide acutely lethal at very low doses?

2019 ◽  
Author(s):  
Kelath Murali Manoj
Keyword(s):  
Reactive Oxygen Species ◽  
Oxygen Consumption ◽  
Oxygen Transport ◽  
Atp Synthesis ◽  
Low Doses ◽  
Oxygen Species ◽  
Mitochondrial Cytochrome ◽  
Futile Cycles ◽  
New Hypothesis ◽  
Mitochondrial Cytochrome Oxidase

Cyanide is conventionally perceived as a binder of heme-Fe centers, disrupting oxygen transport by blood hemoglobin and mitochondrial cytochrome oxidase function. This explanation of toxicity would require millimolar (g/Kg dosage) concentration of cyanide, whereas it is lethal even at micromolar (mg/Kg dosage) ranges. It is long known that oxygen consumption by cells leads to the production of diffusible reactive oxygen species (DROS). Recently, DROS mediated catalytic/metabolic roles were proposed as a physiological source of heat and phosphorylation of ADP within mitochondria. In this purview, it is hypothesized herein that cyanide uses the catalytic DROS via futile cycles, stopping ATP-synthesis and thus killing cells. A quantitative mechanistic perspective delineating the old and new explanations is provided herein. Further, experimental modalities and predictable outcomes are detailed to test the new hypothesis.

Abstract 16: Progressive Alterations Of Mitochondrial Bioenergetics In The Kidney During The Development Of Salt-induced Hypertension

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Namrata Tomar ◽  
Sunil M Kandel ◽  
Xiao Zhang ◽  
Nadezhda Zheleznova ◽  
Allen W Cowley ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Complex Disease ◽  
Atp Synthesis ◽  
Control Group ◽  
Mitochondrial Uncoupling ◽  
Knock Out ◽  
Atp Production ◽  
Consumption Rates ◽  
Mitochondrial Efficiency ◽  
Salt Sensitive Hypertension

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 hypertension has not been characterized. The present study determined changes of OxPhos in kidneys of Dahl salt-sensitive (SS) rats before (0.4% NaCl diet; LS) and after switching to a high salt diet (4.0% NaCl; HS) during the development of hypertension. Mitochondria were isolated from the outer medulla (OM) and cortex of the kidney of SS rats fed a LS diet since weaning and studied at days 3, 7, 14 & 21 of a HS diet feeding. Oxygen consumption rates (OCR) were measured in mitochondria energized with pyruvate + malate as substrates for three different respiratory states using an Oroboros Oxygraph-2k Instrument. This includes i) leak state (in the absence of ADP), ii) ADP-stimulated state, and iii) uncoupled state (in the presence of an uncoupler FCCP). A biphasic pattern of ADP-stimulated OCR with progressive uncoupling was observed in both the renal OM and cortex. Mitochondrial efficiency for ATP synthesis was increased in the early phases of hypertension (3 & 7 days) but was severely compromised in the established phases of hypertension (14 & 21 days). This decreased mitochondrial efficiency was associated with uncoupling of OxPhos and high levels of oxidative stress which we hypothesized were due to mitochondrial ROS stimulation of membrane NOXs. To test this, experiments were performed in SS rats with double knock out (DKO) of the cytosolic subunit of NOX2 (p67 phox ) and NOX4 (SS p67phox-/-/Nox4-/- ). DKO SS rats were fed a HS diet and OCR of renal cortical and OM mitochondria was determined at days 7 and 14. In contrast to SS rats, the DKO SS rats fed a HS diet showed no significant differences in mitochondrial OCR in the cortex or OM, nor to a control group maintained on a LS diet. HS diet in SS rats initially increases the efficiency of renal cortical and medullary mitochondrial ATP production (days 1-7) followed by an enhanced ROS production with mitochondrial uncoupling and reduced efficiency of ATP production by the third week.

scholarly journals Kidney-specific genetic deletion of both AMPK α-subunits causes salt and water wasting

2017 ◽  
Vol 312 (2) ◽  
pp. F352-F365 ◽  
Author(s):  
Yoskaly Lazo-Fernández ◽  
Goretti Baile ◽  
Patricia Meade ◽  
Pilar Torcal ◽  
Laura Martínez ◽  
...  
Keyword(s):  
Energy Homeostasis ◽  
Extracellular Volume ◽  
Atp Synthesis ◽  
Renal Handling ◽  
Salt Wasting ◽  
Cell Energy ◽  
Ampk Activity ◽  
Genetic Deletion

AMP-activated kinase (AMPK) controls cell energy homeostasis by modulating ATP synthesis and expenditure. In vitro studies have suggested AMPK may also control key elements of renal epithelial electrolyte transport but in vivo physiological confirmation is still insufficient. We studied sodium renal handling and extracellular volume regulation in mice with genetic deletion of AMPK catalytic subunits. AMPKα1 knockout (KO) mice exhibit normal renal sodium handling and a moderate antidiuretic state. This is accompanied by higher urinary aldosterone excretion rates and reduced blood pressure. Plasma volume, however, was found to be increased compared with wild-type mice. Thus blood volume is preserved despite a significantly lower hematocrit. The lack of a defect in renal function in AMPKα1 KO mice could be explained by a compensatory upregulation in AMPK α2-subunit. Therefore, we used the Cre-loxP system to knock down AMPKα2 expression in renal epithelial cells. Combining this approach with the systemic deletion of AMPKα1 we achieved reduced renal AMPK activity, accompanied by a shift to a moderate water- and salt-wasting phenotype. Thus we confirm the physiologically relevant role of AMPK in the kidney. Furthermore, our results indicate that in vivo AMPK activity stimulates renal sodium and water reabsorption.

scholarly journals ADP-ribose derived Nuclear ATP is Required for Chromatin Remodeling and Hormonal Gene Regulation (97 charact)

2014 ◽  
Author(s):  
Roni H. G. Wright ◽  
Francois LeDily ◽  
Daniel Soronellas ◽  
Andy Pohl ◽  
Jaume Bonet ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Gene Regulation ◽  
Chromatin Remodeling ◽  
Atp Synthesis ◽  
List Type ◽  
Cell Nuclei ◽  
Energy Consuming ◽  
Regulation Changes ◽  
Nuclear Processes ◽  
Hydrolysis Of

Highlights–Hormonal gene regulation requires synthesis of PAR and its degradation to ADP-ribose by PARG–ADP-ribose is converted to ATP in the cell nuclei by hormone-activated NUDIX5/NUDT5–Blocking nuclear ATP formation precludes hormone-induced chromatin remodeling, gene regulation and cell proliferationSummaryKey nuclear processes in eukaryotes including DNA replication or repair and gene regulation require extensive chromatin remodeling catalyzed by energy consuming enzymes. How the energetic demands of such processes are ensured in response to rapid stimuli remains unclear. We have analyzed this question in the context of the massive gene regulation changes induced by progestins in breast cancer cells and found that ATP is generated in the cell nucleus via the hydrolysis of poly-ADP-ribose to ADP-ribose. Nuclear ATP synthesis requires the combined enzymatic activities of PARP1, PARG and NUDIX5/NUDT5. Although initiated via mitochondrial derived ATP, the nuclear source of ATP is essential for hormone induced chromatin remodeling, gene regulation and cell proliferation and may also participate in DNA repair. This novel pathway reveals exciting avenues of research for drug development.

scholarly journals Rotary substates of mitochondrial ATP synthase reveal the basis of flexible F1-Focoupling

Science ◽  
2019 ◽  
Vol 364 (6446) ◽  
pp. eaaw9128 ◽  
Author(s):  
Bonnie J. Murphy ◽  
Niklas Klusch ◽  
Julian Langer ◽  
Deryck J. Mills ◽  
Özkan Yildiz ◽  
...  
Keyword(s):  
Atp Synthase ◽  
Metal Ion ◽  
Three Dimensional ◽  
Atp Synthesis ◽  
Access Channel ◽  
Dimensional Classification ◽  
Ring Rotation ◽  
Mitochondrial Atp Synthase ◽  
Central Stalk ◽  
Energy Consuming

F1Fo–adenosine triphosphate (ATP) synthases make the energy of the proton-motive force available for energy-consuming processes in the cell. We determined the single-particle cryo–electron microscopy structure of active dimeric ATP synthase from mitochondria ofPolytomellasp. at a resolution of 2.7 to 2.8 angstroms. Separation of 13 well-defined rotary substates by three-dimensional classification provides a detailed picture of the molecular motions that accompanyc-ring rotation and result in ATP synthesis. Crucially, the F1head rotates along with the central stalk andc-ring rotor for the first ~30° of each 120° primary rotary step to facilitate flexible coupling of the stoichiometrically mismatched F1and Fosubcomplexes. Flexibility is mediated primarily by the interdomain hinge of the conserved OSCP subunit. A conserved metal ion in the proton access channel may synchronizec-ring protonation with rotation.

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