scholarly journals Mitochondrial flashes regulate ATP homeostasis in the heart

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Xianhua Wang ◽  
Xing Zhang ◽  
Di Wu ◽  
Zhanglong Huang ◽  
Tingting Hou ◽  
...  
Keyword(s):  
Essential Role ◽  
Eukaryotic Cells ◽  
Dynamic Activity ◽  
F1fo Atp Synthase ◽  
Set Point ◽  
Atp Production ◽  
Homeostatic Function ◽  
Mammalian Myocardium ◽  
Proton Leakage ◽  
Atp Supply

The maintenance of a constant ATP level (‘set-point’) is a vital homeostatic function shared by eukaryotic cells. In particular, mammalian myocardium exquisitely safeguards its ATP set-point despite 10-fold fluctuations in cardiac workload. However, the exact mechanisms underlying this regulation of ATP homeostasis remain elusive. Here we show mitochondrial flashes (mitoflashes), recently discovered dynamic activity of mitochondria, play an essential role for the auto-regulation of ATP set-point in the heart. Specifically, mitoflashes negatively regulate ATP production in isolated respiring mitochondria and, their activity waxes and wanes to counteract the ATP supply-demand imbalance caused by superfluous substrate and altered workload in cardiomyocytes. Moreover, manipulating mitoflash activity is sufficient to inversely shift the otherwise stable ATP set-point. Mechanistically, the Bcl-xL-regulated proton leakage through F1Fo-ATP synthase appears to mediate the coupling between mitoflash production and ATP set-point regulation. These findings indicate mitoflashes appear to constitute a digital auto-regulator for ATP homeostasis in the heart.

scholarly journals Liquid–liquid phase separation in human health and diseases

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Bin Wang ◽  
Lei Zhang ◽  
Tong Dai ◽  
Ziran Qin ◽  
Huasong Lu ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Human Health ◽  
Essential Role ◽  
Current Knowledge ◽  
Vital Role ◽  
Liquid Phase Separation ◽  
Eukaryotic Cells ◽  
Liquid Liquid Phase Separation

AbstractEmerging evidence suggests that liquid–liquid phase separation (LLPS) represents a vital and ubiquitous phenomenon underlying the formation of membraneless organelles in eukaryotic cells (also known as biomolecular condensates or droplets). Recent studies have revealed evidences that indicate that LLPS plays a vital role in human health and diseases. In this review, we describe our current understanding of LLPS and summarize its physiological functions. We further describe the role of LLPS in the development of human diseases. Additionally, we review the recently developed methods for studying LLPS. Although LLPS research is in its infancy—but is fast-growing—it is clear that LLPS plays an essential role in the development of pathophysiological conditions. This highlights the need for an overview of the recent advances in the field to translate our current knowledge regarding LLPS into therapeutic discoveries.

The Wiskott-Aldrich Syndrome (WAS): Studies On A Possible Defect In Mitochondrial ATP Regeneration In Platelets

1981 ◽  
Author(s):  
W van Brederode ◽  
G Gorter ◽  
J W N Akkerman
Keyword(s):  
Co2 Production ◽  
Bleeding Tendency ◽  
Atp Level ◽  
Atp Production ◽  
Clinically Normal ◽  
Platelet Defects ◽  
Atp Supply ◽  
Induced Aggregation ◽  
Normal Controls ◽  
Atp Regeneration

WAS is a severe, X-linked disorder, characterized by eczema, immunodeficiency and an increased bleeding tendency caused by thrombocytopenia and platelet malfunction. There is a diminished epinephrine-induced aggregation response and an abnormal mitochondrial CO2 production during platelet activation. From this, Shapiro et al (The Lancet 1978) concluded that WAS-platelets have a defect in mitochondrial ATP regeneration, which could be employed for detection of WAS- carriers, who are clinically normal and have only minor platelet defects. The test consists of an epinephrine-induced aggregation in the presence of an inhibitor of glycolytic ATP production (deoxyglucose, 2 DG), and showed impaired second wave aggregation in obligate carriers but not in normal controls. We tested 4 unrelated obligate WAS-carriers and found impaired aggregations in all. Five out of 7 female relatives also showed aggregation abnormalities, suggestive for WAS-carriership. However, in 8 out of 15 normal controls (males and females) the test was also positive. The nature of a possible defect in mitochondrial ATP supply was further studied in gel-filtered platelets by analyzing the metabolic ATP level before and during epinephrine-induced aggregation in the presence of inhibitors of glycolysis and glycogenoly- sis and during incubation in substrate-depleted medium. These studies showed that mitochondrial energy generation depended on sugar supply either from glycolysis or glycoge- nolysis and was unable to maintain a normal metabolic ATP level when these pathways were inhibited. Incubation with 2DG led to a fall in metabolic ATP and - consequently - to an impaired epinephrine-induced aggregation. The fall of metabolic ATP (2DG present) was much steeper in platelets from 2 unrelated WAS-patients than in cells from normal controls; most (but not all) obligate carriers showed intermediate values. It is concluded that the impaired epinephrine-induced aggregation in the presence of 2DG in WAS reflects disturbances in ATP homeostasis, which are consistent with a mitochondrial defect.

Structure of the bovine COPI δ subunit μ homology domain at 2.15 Å resolution

2015 ◽  
Vol 71 (6) ◽  
pp. 1328-1334 ◽  
Author(s):  
Avital Lahav ◽  
Haim Rozenberg ◽  
Anna Parnis ◽  
Dan Cassel ◽  
Noam Adir
Keyword(s):  
Crystal Structure ◽  
Essential Role ◽  
Structural Similarity ◽  
Binding Specificity ◽  
Potential Effect ◽  
Eukaryotic Cells ◽  
Asymmetric Unit ◽  
Β Sheets ◽  
Secretory System ◽  
Structural Homologue

The heptameric COPI coat (coatomer) plays an essential role in vesicular transport in the early secretory system of eukaryotic cells. While the structures of some of the subunits have been determined, that of the δ-COP subunit has not been reported to date. The δ-COP subunit is part of a subcomplex with structural similarity to tetrameric clathrin adaptors (APs), where δ-COP is the structural homologue of the AP μ subunit. Here, the crystal structure of the μ homology domain (MHD) of δ-COP (δ-MHD) obtained by phasing using a combined SAD–MR method is presented at 2.15 Å resolution. The crystallographic asymmetric unit contains two monomers that exhibit short sections of disorder, which may allude to flexible regions of the protein. The δ-MHD is composed of two subdomains connected by unstructured linkers. Comparison between this structure and those of known MHD domains from the APs shows significant differences in the positions of specific loops and β-sheets, as well as a more general change in the relative positions of the protein subdomains. The identified difference may be the major source of cargo-binding specificity. Finally, the crystal structure is used to analyze the potential effect of the I422T mutation in δ-COP previously reported to cause a neurodegenerative phenotype in mice.

Ca2+-mobilizing agonists increase mitochondrial ATP production to accelerate cytosolic Ca2+removal: aberrations in human complex I deficiency

2006 ◽  
Vol 291 (2) ◽  
pp. C308-C316 ◽  
Author(s):  
Henk-Jan Visch ◽  
Werner J. H. Koopman ◽  
Dimphy Zeegers ◽  
Sjenet E. van Emst-de Vries ◽  
Frank J. M. van Kuppeveld ◽  
...  
Keyword(s):  
Digital Imaging ◽  
Complex I ◽  
Removal Rate ◽  
Mitochondrial Matrix ◽  
Atp Production ◽  
Complex I Deficiency ◽  
Deficient Patient ◽  
Atp Supply ◽  
Human Complex

Previously, we reported that both the bradykinin (Bk)-induced increase in mitochondrial ATP concentration ([ATP]M) and the rate of cytosolic Ca2+removal are significantly decreased in skin fibroblasts from a patient with an isolated complex I deficiency. Here we demonstrate that the mitochondrial Ca2+indicator rhod-2 can be used to selectively buffer the Bk-induced increase in mitochondrial Ca2+concentration ([Ca2+]M) and, consequently, the Ca2+-stimulated increase in [ATP]M, thus allowing studies of how the increase in [ATP]Mand the cytosolic Ca2+removal rate are related. Luminometry of healthy fibroblasts expressing either aequorin or luciferase in the mitochondrial matrix showed that rhod-2 dose dependently decreased the Bk-induced increase in [Ca2+]Mand [ATP]Mby maximally 80 and 90%, respectively. Digital imaging microscopy of cells coloaded with the cytosolic Ca2+indicator fura-2 revealed that, in parallel, rhod-2 maximally decreased the cytosolic Ca2+removal rate by 20%. These findings demonstrate that increased mitochondrial ATP production is required for accelerating cytosolic Ca2+removal during stimulation with a Ca2+-mobilizing agonist. In contrast, complex I-deficient patient fibroblasts displayed a cytosolic Ca2+removal rate that was already decreased by 40% compared with healthy fibroblasts. Rhod-2 did not further decrease this rate, indicating the absence of mitochondrial ATP supply to the cytosolic Ca2+pumps. This work reveals the usefulness of rhodamine-based Ca2+indicators in examining the role of intramitochondrial Ca2+in mitochondrial (patho) physiology.

Modeling the effects of hypoxia on ATP turnover in exercising muscle

1992 ◽  
Vol 73 (2) ◽  
pp. 737-742 ◽  
Author(s):  
P. G. Arthur ◽  
M. C. Hogan ◽  
D. E. Bebout ◽  
P. D. Wagner ◽  
P. W. Hochachka
Keyword(s):  
Oxygen Consumption ◽  
Metabolic Control ◽  
Lactate Production ◽  
Atp Synthesis ◽  
Atp Production ◽  
Atp Turnover ◽  
Model Based ◽  
The Face ◽  
Energetic State ◽  
Atp Supply

Most models of metabolic control concentrate on the regulation of ATP production and largely ignore the regulation of ATP demand. We describe a model, based on the results of Hogan et al. (J. Appl. Physiol. 73: 728–736, 1992), that incorporates the effects of ATP demand. The model is developed from the premise that a unique set of intracellular conditions can be measured at each level of ATP turnover and that this relationship is best described by energetic state. Current concepts suggest that cells are capable of maintaining oxygen consumption in the face of declines in the concentration of oxygen through compensatory changes in cellular metabolites. We show that these compensatory changes can cause significant declines in ATP demand and result in a decline in oxygen consumption and ATP turnover. Furthermore we find that hypoxia does not directly affect the rate of anaerobic ATP synthesis and associated lactate production. Rather, lactate production appears to be related to energetic state, whatever the PO2. The model is used to describe the interaction between ATP demand and ATP supply in determining final ATP turnover.

Inhibition of energy-producing pathways of HepG2 cells by 3-bromopyruvate1

2009 ◽  
Vol 417 (3) ◽  
pp. 717-726 ◽  
Author(s):  
Ana Paula Pereira Da Silva ◽  
Tatiana El-Bacha ◽  
Nattascha Kyaw ◽  
Reinaldo Sousa Dos Santos ◽  
Wagner Seixas Da-Silva ◽  
...  
Keyword(s):  
Oxygen Consumption ◽  
Succinate Dehydrogenase ◽  
Hepg2 Cells ◽  
Lactate Production ◽  
Phosphoglycerate Kinase ◽  
Atp Production ◽  
Hepatocellular Carcinomas ◽  
Short Period ◽  
Combined Action ◽  
Proton Leakage

3-BrPA (3-bromopyruvate) is an alkylating agent with anti-tumoral activity on hepatocellular carcinoma. This compound inhibits cellular ATP production owing to its action on glycolysis and oxidative phosphorylation; however, the specific metabolic steps and mechanisms of 3-BrPA action in human hepatocellular carcinomas, particularly its effects on mitochondrial energetics, are poorly understood. In the present study it was found that incubation of HepG2 cells with a low concentration of 3-BrPA for a short period (150 μM for 30 min) significantly affected both glycolysis and mitochondrial respiratory functions. The activity of mitochondrial hexokinase was not inhibited by 150 μM 3-BrPA, but this concentration caused more than 70% inhibition of GAPDH (glyceraldehyde-3-phosphate dehydrogenase) and 3-phosphoglycerate kinase activities. Additionally, 3-BrPA treatment significantly impaired lactate production by HepG2 cells, even when glucose was withdrawn from the incubation medium. Oxygen consumption of HepG2 cells supported by either pyruvate/malate or succinate was inhibited when cells were pre-incubated with 3-BrPA in glucose-free medium. On the other hand, when cells were pre-incubated in glucose-supplemented medium, oxygen consumption was affected only when succinate was used as the oxidizable substrate. An increase in oligomycin-independent respiration was observed in HepG2 cells treated with 3-BrPA only when incubated in glucose-supplemented medium, indicating that 3-BrPA induces mitochondrial proton leakage as well as blocking the electron transport system. The activity of succinate dehydrogenase was inhibited by 70% by 3-BrPA treatment. These results suggest that the combined action of 3-BrPA on succinate dehydrogenase and on glycolysis, inhibiting steps downstream of the phosphorylation of glucose, play an important role in HepG2 cell death.

scholarly journals Proteasome activity is required for the stage-specific transformation of a protozoan parasite.

1996 ◽  
Vol 184 (5) ◽  
pp. 1909-1918 ◽  
Author(s):  
J González ◽  
F J Ramalho-Pinto ◽  
U Frevert ◽  
J Ghiso ◽  
S Tomlinson ◽  
...  
Keyword(s):  
Essential Role ◽  
Morphological Changes ◽  
Protozoan Parasite ◽  
Eukaryotic Cells ◽  
Cysteine Proteinases ◽  
Axenic Medium ◽  
Cytoplasmic Proteins ◽  
Intracellular Parasites

A prominent feature of the life cycle of intracellular parasites is the profound morphological changes they undergo during development in the vertebrate and invertebrate hosts. In eukaryotic cells, most cytoplasmic proteins are degraded in proteasomes. Here, we show that the transformation in axenic medium of trypomastigotes of Trypanosoma cruzi into amastigote-like organisms, and the intracellular development of the parasite from amastigotes into trypomastigotes, are prevented by lactacystin, or by a peptide aldehyde that inhibits proteasome function. Clasto-lactacystin, an inactive analogue of lactacystin, and cell-permeant peptide aldehyde inhibitors of T. cruzi cysteine proteinases have no effect. We have also identified the 20S proteasomes from T. cruzi as a target of lactacystin in vivo. Our results document the essential role of proteasomes in the stage-specific transformation of a protozoan.

scholarly journals Mechanisms of mitochondrial response to variations in energy demand in eukaryotic cells

2007 ◽  
Vol 292 (1) ◽  
pp. C52-C58 ◽  
Author(s):  
Anne Devin ◽  
Michel Rigoulet
Keyword(s):  
Oxidative Phosphorylation ◽  
Energy Demand ◽  
Covalent Modification ◽  
Eukaryotic Cells ◽  
Heart Cells ◽  
Mitochondrial Enzyme ◽  
Atp Production ◽  
Enzyme Content ◽  
Mitochondrial Atp Synthase ◽  
Kinetic Regulation

This review focuses on the different mechanisms involved in the adjustment of mitochondrial ATP production to cellular energy demand. The oxidative phosphorylation steady state at constant mitochondrial enzyme content can vary in response to energy demand. However, such an adaptation is tightly linked to a modification in both oxidative phosphorylation yield and phosphate potential and is obviously very limited in eukaryotic cells. We describe the three main mechanisms involved in mitochondrial response to energy demand. In heart cells, a short-term adjustment can be reached mainly through metabolic signaling via phosphotransfer networks by the compartmentalized energy transfer and signal transmission. In such a complex regulatory mechanism, Ca2+signaling participates in activation of matricial dehydrogenases as well as mitochondrial ATP synthase. These processes allow a large increase in ATP production rate without an important modification in thermodynamic forces. For a long-term adaptation, two main mechanisms are involved: modulation of the mitochondrial enzyme content as a function of energy demand and/or kinetic regulation by covalent modifications (phosphorylations) of some respiratory chain complex subunits. Regardless of the mechanism involved (kinetic regulation by covalent modification or adjustment of mitochondrial enzyme content), the cAMP signaling pathway plays a major role in molecular signaling, leading to the mitochondrial response. We discuss the energetic advantages of these mechanisms.

scholarly journals Cytochrome c Oxidase at Full Thrust: Regulation and Biological Consequences to Flying Insects

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 470
Author(s):  
Rafael Mesquita ◽  
Alessandro Gaviraghi ◽  
Renata Gonçalves ◽  
Marcos Vannier-Santos ◽  
Julio Mignaco ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Energy Demand ◽  
Redox Balance ◽  
Mitochondrial Enzymes ◽  
Mitochondrial Energy Metabolism ◽  
Atp Production ◽  
Insect Biology ◽  
Oxidant Production ◽  
Atp Supply

Flight dispersal represents a key aspect of the evolutionary and ecological success of insects, allowing escape from predators, mating, and colonization of new niches. The huge energy demand posed by flight activity is essentially met by oxidative phosphorylation (OXPHOS) in flight muscle mitochondria. In insects, mitochondrial ATP supply and oxidant production are regulated by several factors, including the energy demand exerted by changes in adenylate balance. Indeed, adenylate directly regulates OXPHOS by targeting both chemiosmotic ATP production and the activities of specific mitochondrial enzymes. In several organisms, cytochrome c oxidase (COX) is regulated at transcriptional, post-translational, and allosteric levels, impacting mitochondrial energy metabolism, and redox balance. This review will present the concepts on how COX function contributes to flying insect biology, focusing on the existing examples in the literature where its structure and activity are regulated not only by physiological and environmental factors but also how changes in its activity impacts insect biology. We also performed in silico sequence analyses and determined the structure models of three COX subunits (IV, VIa, and VIc) from different insect species to compare with mammalian orthologs. We observed that the sequences and structure models of COXIV, COXVIa, and COXVIc were quite similar to their mammalian counterparts. Remarkably, specific substitutions to phosphomimetic amino acids at critical phosphorylation sites emerge as hallmarks on insect COX sequences, suggesting a new regulatory mechanism of COX activity. Therefore, by providing a physiological and bioenergetic framework of COX regulation in such metabolically extreme models, we hope to expand the knowledge of this critical enzyme complex and the potential consequences for insect dispersal.

scholarly journals Possible mechanisms underlying slow component of V̇o2 on-kinetics in skeletal muscle

2015 ◽  
Vol 118 (10) ◽  
pp. 1240-1249 ◽  
Author(s):  
Bernard Korzeniewski ◽  
Jerzy A. Zoladz
Keyword(s):  
Skeletal Muscle ◽  
Creatine Kinase ◽  
Gradual Increase ◽  
Slow Component ◽  
Anaerobic Glycolysis ◽  
Atp Production ◽  
Slow Decrease ◽  
Muscle Ph ◽  
Creatine Kinase Reaction ◽  
Atp Supply

A computer model of a skeletal muscle bioenergetic system is used to study the background of the slow component of oxygen consumption V̇o2 on-kinetics in skeletal muscle. Two possible mechanisms are analyzed: inhibition of ATP production by anaerobic glycolysis by progressive cytosol acidification (together with a slow decrease in ATP supply by creatine kinase) and gradual increase of ATP usage during exercise of constant power output. It is demonstrated that the former novel mechanism is potent to generate the slow component. The latter mechanism further increases the size of the slow component; it also moderately decreases metabolite stability and has a small impact on muscle pH. An increase in anaerobic glycolysis intensity increases the slow component, elevates cytosol acidification during exercise, and decreases phosphocreatine and Pi stability, although slightly increases ADP stability. A decrease in the P/O ratio (ATP molecules/O2 molecules) during exercise cannot also be excluded as a relevant mechanism, although this issue requires further study. It is postulated that both the progressive inhibition of anaerobic glycolysis by accumulating protons (together with a slow decrease of the net creatine kinase reaction rate) and gradual increase of ATP usage during exercise, and perhaps a decrease in P/O, contribute to the generation of the slow component of the V̇o2 on-kinetics in skeletal muscle.

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