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Biochimica Et Biophysica Acta May 2011Heme serves as a co-factor in proteins involved in fundamental biological processes including oxidative metabolism, oxygen storage and transport, signal transduction and... (Review)
Review
Heme serves as a co-factor in proteins involved in fundamental biological processes including oxidative metabolism, oxygen storage and transport, signal transduction and drug metabolism. In addition, heme is important for systemic iron homeostasis in mammals. Heme has important regulatory roles in cell biology, yet excessive levels of intracellular heme are toxic; thus, mechanisms have evolved to control the acquisition, synthesis, catabolism and expulsion of cellular heme. Recently, a number of transporters of heme and heme synthesis intermediates have been described. Here we review aspects of heme metabolism and discuss our current understanding of heme transporters, with emphasis on the function of the cell-surface heme exporter, FLVCR. Knockdown of Flvcr in mice leads to both defective erythropoiesis and disturbed systemic iron homeostasis, underscoring the critical role of heme transporters in mammalian physiology. This article is part of a Special Issue entitled: 11th European Symposium on Calcium.
Topics: Absorption; Animals; Biological Transport; Heme; Heme Oxygenase (Decyclizing); Humans; Intracellular Space; Membrane Transport Proteins
PubMed: 21238504
DOI: 10.1016/j.bbamcr.2011.01.008 -
Cellular and Molecular Life Sciences :... Nov 2009This article outlines the need for a homeostatic response to alterations in cellular oxygenation. It describes work on erythropoietin control that led to the discovery... (Review)
Review
This article outlines the need for a homeostatic response to alterations in cellular oxygenation. It describes work on erythropoietin control that led to the discovery of the hypoxia-inducible transcription factor (HIF-1) and the parallel recognition that this system was responsive to a widespread oxygen-sensing mechanism. Subsequently, multiple HIF isoforms have been shown to have overlapping but non-redundant functions, controlling expression of genes involved in diverse processes such as angiogenesis, vascular tone, metal transport, glycolysis, mitochondrial function, cell growth and survival. The major role of prolyl and asparaginyl hydroxylation in regulating HIFs is described, as well as the identification of PHD1-3 and FIH as the oxygen-sensing enzymes responsible for these hydroxylations. Current understanding of other processes that modulate overall HIF activity, including influences from other signalling mechanisms such as kinases and nitric oxide levels, and the existence of a variety of feedback loops are outlined. The effects of some mutations in this pathway are documented as is knowledge of other substrates for these enzymes. The importance of PHD1-3 and FIH, and the large family of 2-oxoglutarate and iron(II)-dependent dioxygenases of which they are a part, in biology and medicine are discussed.
Topics: Animals; Cell Hypoxia; Humans; Hypoxia-Inducible Factor 1; Mixed Function Oxygenases; Models, Biological; Oxygen; Oxygen Consumption; Protein Isoforms; Transcription Factors
PubMed: 19756382
DOI: 10.1007/s00018-009-0147-7 -
Journal of Molecular Biology Oct 2018The oxidative phosphorylation system contains four respiratory chain complexes that connect the transport of electrons to oxygen with the establishment of an... (Review)
Review
The oxidative phosphorylation system contains four respiratory chain complexes that connect the transport of electrons to oxygen with the establishment of an electrochemical gradient over the inner membrane for ATP synthesis. Due to the dual genetic source of the respiratory chain subunits, its assembly requires a tight coordination between nuclear and mitochondrial gene expression machineries. In addition, dedicated assembly factors support the step-by-step addition of catalytic and accessory subunits as well as the acquisition of redox cofactors. Studies in yeast have revealed the basic principles underlying the assembly pathways. In this review, we summarize work on the biogenesis of the bc complex or complex III, a central component of the mitochondrial energy conversion system.
Topics: Animals; Cell Respiration; Electron Transport; Electron Transport Complex III; Humans; Mitochondria; Mitochondrial Proteins; Oxidative Phosphorylation; Protein Binding; Protein Subunits; Structure-Activity Relationship
PubMed: 29733856
DOI: 10.1016/j.jmb.2018.04.036 -
Advanced Biosystems Aug 2020Poor oxygen transport is a major obstacle currently for 3D microtissue culture platforms, which at this time cannot be grown large enough to be truly physiologically...
Poor oxygen transport is a major obstacle currently for 3D microtissue culture platforms, which at this time cannot be grown large enough to be truly physiologically relevant and replicate adult human organ functions. To overcome internal oxygen transport deficiencies, oxygenating microgels are formed utilizing perfluorocarbon (PFC) modified chitosan and a highly scalable water-in-oil miniemulsion method. Microgels that are on the order of a cell diameter (≈10 µm) are formed allowing them to directly associate with cells when included in 3D spheroid culture, while not being internalized. The presence of immobilized PFCs in these microgels allows for enhancement and tuning of oxygen transport when incorporated into cultured microtissues. As such, it is demonstrated that incorporating oxygenating microgels at ratios ranging from 50:1 to 400:1 (# of cells:# of microgels) into dense human fibroblast-based spheroids facilitated the growth of larger human cell-based spheroids, especially at the highest incorporation percentages (50:1), which lacked defined hypoxic cores. Quantification of total double-stranded (ds)-DNA, a measure of number of live cells, demonstrated similar results to hypoxia quantification, showing more ds-DNA due incorporation of oxygenating microgels. Finally, oxygen concentrations are measured at different depths within spheroids directly and confirmed higher oxygen partial pressures due to chitosan-PFC microspheres.
Topics: Biological Transport; Cell Hypoxia; Chitosan; DNA; Emulsions; Fibroblasts; Fluorocarbons; Foreskin; Halogenation; Humans; Infant, Newborn; Male; Microgels; Oxygen; Primary Cell Culture; Spheroids, Cellular
PubMed: 32686345
DOI: 10.1002/adbi.201900250 -
Journal of Biomechanical Engineering Oct 2012One of the primary limitations of cell therapy for myocardial infarction is the low survival of transplanted cells, with a loss of up to 80% of cells within 3 days of...
One of the primary limitations of cell therapy for myocardial infarction is the low survival of transplanted cells, with a loss of up to 80% of cells within 3 days of delivery. The aims of this study were to investigate the distribution of nutrients and oxygen in infarcted myocardium and to quantify how macromolecular transport properties might affect cell survival. Transmural myocardial infarction was created by controlled cryoablation in pigs. At 30 days post-infarction, oxygen and metabolite levels were measured in the peripheral skeletal muscle, normal myocardium, the infarct border zone, and the infarct interior. The diffusion coefficients of fluorescein or FITC-labeled dextran (0.3-70 kD) were measured in these tissues using fluorescence recovery after photobleaching. The vascular density was measured via endogenous alkaline phosphatase staining. To examine the influence of these infarct conditions on cells therapeutically used in vivo, skeletal myoblast survival and differentiation were studied in vitro under the oxygen and glucose concentrations measured in the infarct tissue. Glucose and oxygen concentrations, along with vascular density were significantly reduced in infarct when compared to the uninjured myocardium and infarct border zone, although the degree of decrease differed. The diffusivity of molecules smaller than 40 kD was significantly higher in infarct center and border zone as compared to uninjured heart. Skeletal myoblast differentiation and survival were decreased stepwise from control to hypoxia, starvation, and ischemia conditions. Although oxygen, glucose, and vascular density were significantly reduced in infarcted myocardium, the rate of macromolecular diffusion was significantly increased, suggesting that diffusive transport may not be inhibited in infarct tissue, and thus the supply of nutrients to transplanted cells may be possible. in vitro studies mimicking infarct conditions suggest that increasing nutrients available to transplanted cells may significantly increase their ability to survive in infarct.
Topics: Animals; Biological Transport; Cell Death; Cell Differentiation; Cell Hypoxia; Cell Line; Cell Proliferation; Diffusion; Glucose; Mice; Myoblasts, Skeletal; Myocardial Infarction; Myocardium; Oxygen; Swine
PubMed: 23083196
DOI: 10.1115/1.4007455 -
Sheng Li Xue Bao : [Acta Physiologica... Apr 2019Drug metabolism is significantly affected under hypoxia environment with changes of pharmacokinetics, expression and function of drug-metabolizing enzymes and... (Review)
Review
Drug metabolism is significantly affected under hypoxia environment with changes of pharmacokinetics, expression and function of drug-metabolizing enzymes and transporters. Studies have shown that hypoxia increases the release of a series of inflammatory cytokines which can modulate drug metabolism. Besides, both hypoxia inducible factor 1α (HIF-1α) and microRNA-mediated pathways play a role in regulating drug metabolism. This article reviewed the impact and single-factor modulating mechanisms of drug metabolism under hypoxia, and put forward the speculation and prospects of multi-factor modulating mechanisms.
Topics: Cell Hypoxia; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Membrane Transport Proteins; MicroRNAs; Pharmaceutical Preparations
PubMed: 31008494
DOI: No ID Found -
IUBMB Life 2007O(2)carriers (extracellular and intracellular as well as monomeric and multimeric) have evolved over the last billion of years, displaying iron and copper reactive... (Review)
Review
O(2)carriers (extracellular and intracellular as well as monomeric and multimeric) have evolved over the last billion of years, displaying iron and copper reactive centers; very different O(2)carriers may co-exist in the same organism. Circulating O(2)carriers, faced to the external environment, are responsible for maintaining an adequate delivery of O(2)to tissues and organs almost independently of the environmental O(2)partial pressure. Then, intracellular globins facilitate O(2)transfer to mitochondria sustaining cellular respiration. Here, molecular aspects of multiple strategies evolved for O(2)transport and delivery are examined, from the simplest myoglobin to the most complex giant O(2)carriers and the red blood cell, mostly focusing on the aspects which have been mainly addressed by the so called 'Rome Group'.
Topics: Animals; Biological Transport; Brain; Models, Molecular; Oxygen; Signal Transduction; Thermodynamics
PubMed: 17701555
DOI: 10.1080/15216540701308424 -
BMC Biochemistry Sep 2015Aberrant mitochondrial function, including excessive reactive oxygen species (ROS) production, has been implicated in the pathogenesis of human diseases. The use of...
BACKGROUND
Aberrant mitochondrial function, including excessive reactive oxygen species (ROS) production, has been implicated in the pathogenesis of human diseases. The use of mitochondrial inhibitors to ascertain the sites in the electron transport chain (ETC) resulting in altered ROS production can be an important tool. However, the response of mouse mitochondria to ETC inhibitors has not been thoroughly assessed. Here we set out to characterize the differences in phenotypic response to ETC inhibitors between the more energetically demanding brain mitochondria and less energetically demanding liver mitochondria in commonly utilized C57BL/6J mice.
RESULTS
We show that in contrast to brain mitochondria, inhibiting distally within complex I or within complex III does not increase liver mitochondrial ROS production supported by complex I substrates, and liver mitochondrial ROS production supported by complex II substrates occurred primarily independent of membrane potential. Complex I, II, and III enzymatic activities and membrane potential were equivalent between liver and brain and responded to ETC. inhibitors similarly. Brain mitochondria exhibited an approximately two-fold increase in complex I and II supported respiration compared with liver mitochondria while exhibiting similar responses to inhibitors. Elevated NADH transport and heightened complex II-III coupled activity accounted for increased complex I and II supported respiration, respectively in brain mitochondria.
CONCLUSIONS
We conclude that important mechanistic differences exist between mouse liver and brain mitochondria and that mouse mitochondria exhibit phenotypic differences compared with mitochondria from other species.
Topics: Animals; Aspartic Acid; Biological Transport; Brain; Cell Respiration; Dicarboxylic Acid Transporters; Electron Transport Chain Complex Proteins; Enzyme Inhibitors; Gene Expression Regulation; Glutamic Acid; Kinetics; Liver; Malates; Membrane Potential, Mitochondrial; Mice; Mitochondria, Liver; NAD; Organ Specificity; Reactive Oxygen Species; Succinic Acid
PubMed: 26358560
DOI: 10.1186/s12858-015-0051-8 -
Biochimica Et Biophysica Acta Oct 2014Calcium homeostasis is central to all cellular functions and has been studied for decades. Calcium acts as a critical second messenger for both extracellular and... (Review)
Review
Calcium homeostasis is central to all cellular functions and has been studied for decades. Calcium acts as a critical second messenger for both extracellular and intracellular signaling and is fundamental in cell life and death decisions (Berridge et al., 2000) [1]. The calcium gradient in the cell is coupled with an inherent ability of the divalent cation to reversibly bind multiple target biological molecules to generate an extremely versatile signaling system [2]. Calcium signals are used by the cell to control diverse processes such as development, neurotransmitter release, muscle contraction, metabolism, autophagy and cell death. "Cellular calcium overload" is detrimental to cellular health, resulting in massive activation of proteases and phospholipases leading to cell death (Pinton et al., 2008) [3]. Historically, cell death associated with calcium ion perturbations has been primarily recognized as necrosis. Recent evidence clearly associates changes in calcium ion concentrations with more sophisticated forms of cellular demise, including apoptosis (Kruman et al., 1998; Tombal et al., 1999; Lynch et al., 2000; Orrenius et al., 2003) [4-7]. Although the endoplasmic reticulum (ER) serves as the primary calcium store in the metazoan cell, dynamic calcium release to the cytosol, mitochondria, nuclei and other organelles orchestrate diverse coordinated responses. Most evidence supports that calcium transport from the ER to mitochondria plays a significant role in regulating cellular bioenergetics, production of reactive oxygen species, induction of autophagy and apoptosis. Recently, molecular identities that mediate calcium traffic between the ER and mitochondria have been discovered (Mallilankaraman et al., 2012a; Mallilankaraman et al., 2012b; Sancak et al., 2013)[8-10]. The next questions are how they are regulated for exquisite tight control of ER-mitochondrial calcium dynamics. This review attempts to summarize recent advances in the role of calcium in regulation of ER and mitochondrial function. This article is part of a Special Issue entitled: Calcium signaling in health and disease. Guest Editors: Geert Bultynck, Jacques Haiech, Claus W. Heizmann, Joachim Krebs, and Marc Moreau.
Topics: Animals; Calcium; Calcium Signaling; Cell Death; Endoplasmic Reticulum; Energy Metabolism; Gene Expression; Humans; Mitochondria; Mitochondrial Membrane Transport Proteins; Protein Transport
PubMed: 24690484
DOI: 10.1016/j.bbamcr.2014.03.022 -
Biochimica Et Biophysica Acta Aug 2016Glutamate elicits Ca(2+) signals and workloads that regulate neuronal fate both in physiological and pathological circumstances. Oxidative phosphorylation is required in... (Review)
Review
Glutamate elicits Ca(2+) signals and workloads that regulate neuronal fate both in physiological and pathological circumstances. Oxidative phosphorylation is required in order to respond to the metabolic challenge caused by glutamate. In response to physiological glutamate signals, cytosolic Ca(2+) activates respiration by stimulation of the NADH malate-aspartate shuttle through Ca(2+)-binding to the mitochondrial aspartate/glutamate carrier (Aralar/AGC1/Slc25a12), and by stimulation of adenine nucleotide uptake through Ca(2+) binding to the mitochondrial ATP-Mg/Pi carrier (SCaMC-3/Slc25a23). In addition, after Ca(2+) entry into the matrix through the mitochondrial Ca(2+) uniporter (MCU), it activates mitochondrial dehydrogenases. In response to pathological glutamate stimulation during excitotoxicity, Ca(2+) overload, reactive oxygen species (ROS), mitochondrial dysfunction and delayed Ca(2+) deregulation (DCD) lead to neuronal death. Glutamate-induced respiratory stimulation is rapidly inactivated through a mechanism involving Poly (ADP-ribose) Polymerase-1 (PARP-1) activation, consumption of cytosolic NAD(+), a decrease in matrix ATP and restricted substrate supply. Glutamate-induced Ca(2+)-activation of SCaMC-3 imports adenine nucleotides into mitochondria, counteracting the depletion of matrix ATP and the impaired respiration, while Aralar-dependent lactate metabolism prevents substrate exhaustion. A second mechanism induced by excitotoxic glutamate is permeability transition pore (PTP) opening, which critically depends on ROS production and matrix Ca(2+) entry through the MCU. By increasing matrix content of adenine nucleotides, SCaMC-3 activity protects against glutamate-induced PTP opening and lowers matrix free Ca(2+), resulting in protracted appearance of DCD and protection against excitotoxicity in vitro and in vivo, while the lack of lactate protection during in vivo excitotoxicity explains increased vulnerability to kainite-induced toxicity in Aralar +/- mice. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi.
Topics: Adenosine Triphosphate; Animals; Antiporters; Calcium; Calcium Channels; Cell Respiration; Gene Expression; Glutamic Acid; Mice; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Mitochondrial Proteins; Neurons; Oxidative Phosphorylation; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases; Primary Cell Culture; Reactive Oxygen Species; Signal Transduction
PubMed: 27060251
DOI: 10.1016/j.bbabio.2016.04.003