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Biomolecules Jul 2023Iron is an essential transition metal for its involvement in several crucial biological functions, the most notable being oxygen storage and transport. Due to its high... (Review)
Review
Iron is an essential transition metal for its involvement in several crucial biological functions, the most notable being oxygen storage and transport. Due to its high reactivity and potential toxicity, intracellular and extracellular iron levels must be tightly regulated. This is achieved through transport systems that mediate cellular uptake and efflux both at the level of the plasma membrane and on the membranes of lysosomes, endosomes and mitochondria. Among these transport systems, the key players are ferroportin, the only known transporter mediating iron efflux from cells; DMT1, ZIP8 and ZIP14, which on the contrary, mediate iron influx into the cytoplasm, acting on the plasma membrane and on the membranes of lysosomes and endosomes; and mitoferrin, involved in iron transport into the mitochondria for heme synthesis and Fe-S cluster assembly. The focus of this review is to provide an updated view of the physiological role of these membrane proteins and of the pathologies that arise from defects of these transport systems.
Topics: Iron; Biological Transport; Membrane Proteins; Cell Membrane; Lysosomes
PubMed: 37627237
DOI: 10.3390/biom13081172 -
Biochimica Et Biophysica Acta Oct 2016In this review we discuss the structure and functions of the aspartate/glutamate carriers (AGC1-aralar and AGC2-citrin). Those proteins supply the aspartate synthesized... (Review)
Review
In this review we discuss the structure and functions of the aspartate/glutamate carriers (AGC1-aralar and AGC2-citrin). Those proteins supply the aspartate synthesized within mitochondrial matrix to the cytosol in exchange for glutamate and a proton. A structure of an AGC carrier is not available yet but comparative 3D models were proposed. Moreover, transport assays performed by using the recombinant AGC1 and AGC2, reconstituted into liposome vesicles, allowed to explore the kinetics of those carriers and to reveal their specific transport properties. AGCs participate to a wide range of cellular functions, as the control of mitochondrial respiration, calcium signaling and antioxydant defenses. AGC1 might also play peculiar tissue-specific functions, as it was found to participate to cell-to-cell metabolic symbiosis in the retina. On the other hand, AGC1 is involved in the glutamate-mediated excitotoxicity in neurons and AGC gene or protein alterations were discovered in rare human diseases. Accordingly, a mice model of AGC1 gene knock-out presented with growth delay and generalized tremor, with myelinisation defects. More recently, AGC was proposed to play a crucial role in tumor metabolism as observed from metabolomic studies showing that the asparate exported from the mitochondrion by AGC1 is employed in the regeneration of cytosolic glutathione. Therefore, given the central role of AGCs in cell metabolism and human pathology, drug screening are now being developed to identify pharmacological modulators of those carriers. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Pierre Sonveaux, Pierre Maechler and Jean-Claude Martinou.
Topics: Amino Acid Sequence; Animals; Aspartic Acid; Biological Transport, Active; Calcium-Binding Proteins; Cattle; Consensus Sequence; Glutamic Acid; Humans; Malates; Mice; Mitochondria; Mitochondrial Membrane Transport Proteins; Models, Molecular; NAD; Neoplasm Proteins; Organ Specificity; Organic Anion Transporters; Oxidation-Reduction; Protein Conformation; Sequence Alignment; Sequence Homology, Amino Acid
PubMed: 27132995
DOI: 10.1016/j.bbamcr.2016.04.011 -
Plant Physiology Apr 2023Plant respiration is a foundational biological process with the potential to be optimized to improve crop yield. To understand and manipulate the outputs of respiration,... (Review)
Review
Plant respiration is a foundational biological process with the potential to be optimized to improve crop yield. To understand and manipulate the outputs of respiration, the inputs of respiration-respiratory substrates-need to be probed in detail. Mitochondria house substrate catabolic pathways and respiratory machinery, so transport into and out of these organelles plays an important role in committing substrates to respiration. The large number of mitochondrial carriers and catabolic pathways that remain unidentified hinder this process and lead to confusion about the identity of direct and indirect respiratory substrates in plants. The sources and usage of respiratory substrates vary and are increasing found to be highly regulated based on cellular processes and environmental factors. This review covers the use of direct respiratory substrates following transport through mitochondrial carriers and catabolism under normal and stressed conditions. We suggest the introduction of enzymes not currently found in plant mitochondria to enable serine and acetate to be direct respiratory substrates in plants. We also compare respiratory substrates by assessing energetic yields, availability in cells, and their full or partial oxidation during cell catabolism. This information can assist in decisions to use synthetic biology approaches to alter the range of respiratory substrates in plants. As a result, respiration could be optimized by introducing, improving, or controlling specific mitochondrial transporters and mitochondrial catabolic pathways.
Topics: Mitochondria; Cell Respiration; Oxidation-Reduction; Energy Metabolism; Plants; Respiration
PubMed: 36573332
DOI: 10.1093/plphys/kiac599 -
The Journal of Physiology Mar 2021Timely delivery of oxygen (O ) to tissue mitochondria is so essential that elaborate circulatory systems have evolved to minimize diffusion distances within tissue. Yet,... (Review)
Review
Timely delivery of oxygen (O ) to tissue mitochondria is so essential that elaborate circulatory systems have evolved to minimize diffusion distances within tissue. Yet, knowledge is surprisingly limited regarding the diffusion pathway between blood capillaries and tissue mitochondria. An established and growing body of work examines the influence cellular and extracellular structures may have on subcellular oxygen availability. This brief review discusses the physiological and pathophysiological significance of oxygen availability, highlights recent computer modelling studies of transport at the cell-membrane level, and considers alternative diffusion pathways within tissue. Experimental and computer modelling studies suggest that oxygen diffusion may be accelerated by cellular lipids, relative to cytosolic and interstitial fluids. Such acceleration, or 'channelling', would occur due to greatly enhanced oxygen solubility in lipids, especially near the midplane of lipid bilayers. Rapid long-range movement would be promoted by anisotropically enhanced lateral diffusion of oxygen along the midplane and by junctions holding lipid structures in close proximity to one another throughout the tissue. Clarifying the biophysical mechanism of oxygen transport within tissue will shed light on limitations and opportunities in tumour radiotherapy and tissue engineering.
Topics: Capillaries; Cell Membrane Permeability; Diffusion; Mitochondria; Oxygen; Oxygen Consumption
PubMed: 33215707
DOI: 10.1113/JP278815 -
Biochimica Et Biophysica Acta Dec 2016Lonidamine (LND) was initially introduced as an antispermatogenic agent. It was later found to have anticancer activity sensitizing tumors to chemo-, radio-, and... (Review)
Review
Lonidamine (LND) was initially introduced as an antispermatogenic agent. It was later found to have anticancer activity sensitizing tumors to chemo-, radio-, and photodynamic-therapy and hyperthermia. Although the mechanism of action remained unclear, LND treatment has been known to target metabolic pathways in cancer cells. It has been reported to alter the bioenergetics of tumor cells by inhibiting glycolysis and mitochondrial respiration, while indirect evidence suggested that it also inhibited l-lactic acid efflux from cells mediated by members of the proton-linked monocarboxylate transporter (MCT) family and also pyruvate uptake into the mitochondria by the mitochondrial pyruvate carrier (MPC). Recent studies have demonstrated that LND potently inhibits MPC activity in isolated rat liver mitochondria (K 2.5μM) and cooperatively inhibits l-lactate transport by MCT1, MCT2 and MCT4 expressed in Xenopus laevis oocytes with K and Hill coefficient values of 36-40μM and 1.65-1.85, respectively. In rat heart mitochondria LND inhibited the MPC with similar potency and uncoupled oxidation of pyruvate was inhibited more effectively (IC~7μM) than other substrates including glutamate (IC~20μM). LND inhibits the succinate-ubiquinone reductase activity of respiratory Complex II without fully blocking succinate dehydrogenase activity. LND also induces cellular reactive oxygen species through Complex II and has been reported to promote cell death by suppression of the pentose phosphate pathway, which resulted in inhibition of NADPH and glutathione generation. We conclude that MPC inhibition is the most sensitive anti-tumour target for LND, with additional inhibitory effects on MCT-mediated l-lactic acid efflux, Complex II and glutamine/glutamate oxidation.
Topics: Animals; Antineoplastic Agents; Hexokinase; Humans; Hydrogen-Ion Concentration; Indazoles; Membrane Transport Proteins; Mitochondria; Mitochondrial Membrane Transport Proteins; Monocarboxylic Acid Transporters; Pyruvic Acid
PubMed: 27497601
DOI: 10.1016/j.bbcan.2016.08.001 -
Seminars in Cancer Biology May 2024Mitochondria are the major sink for oxygen in the cell, consuming it during ATP production. Therefore, when environmental oxygen levels drop in the tumor, significant... (Review)
Review
Mitochondria are the major sink for oxygen in the cell, consuming it during ATP production. Therefore, when environmental oxygen levels drop in the tumor, significant adaptation is required. Mitochondrial activity is also a major producer of biosynthetic precursors and a regulator of cellular oxidative and reductive balance. Because of the complex biochemistry, mitochondrial adaptation to hypoxia occurs through multiple mechanisms and has significant impact on other cellular processes such as macromolecule synthesis and gene regulation. In tumor hypoxia, mitochondria shift their location in the cell and accelerate the fission and quality control pathways. Hypoxic mitochondria also undergo significant changes to fundamental metabolic pathways of carbon metabolism and electron transport. These metabolic changes further impact the nuclear epigenome because mitochondrial metabolites are used as enzymatic substrates for modifying chromatin. This coordinated response delivers physiological flexibility and increased tumor cell robustness during the environmental stress of low oxygen.
Topics: Humans; Mitochondria; Hypoxia; Oxygen; Cell Hypoxia; Stress, Physiological; Adaptation, Physiological
PubMed: 38556040
DOI: 10.1016/j.semcancer.2024.03.004 -
Current Opinion in Cell Biology Aug 2019Copper is an essential micronutrient required for oxygen-dependent enzymes, yet excess of the metal is a toxicant. The tug-of-war between these copper activities is... (Review)
Review
Copper is an essential micronutrient required for oxygen-dependent enzymes, yet excess of the metal is a toxicant. The tug-of-war between these copper activities is balanced by chaperones and membrane transporters, which control copper distribution and availability. The P-type ATPase transporters, ATP7A and ATP7B, regulate cytoplasmic copper by pumping copper out of cells or into the endomembrane system. Mutations in ATP7A and ATP7B cause diseases that share neuropsychiatric phenotypes, which are similar to phenotypes observed in mutations affecting cytoplasmic trafficking complexes required for ATP7A/B dynamics. Here, we discuss evidence indicating that phenotypes associated to genetic defects in trafficking complexes, such as retromer and the adaptor complex AP-1, result in part from copper dyshomeostasis due to mislocalized ATP7A and ATP7B.
Topics: Animals; Copper Transport Proteins; Copper-Transporting ATPases; Humans; Mitochondria; Mutation; Parkinson Disease; Protein Transport
PubMed: 30928671
DOI: 10.1016/j.ceb.2019.02.009 -
Metallomics : Integrated Biometal... Sep 2016Copper (Cu) is indispensible for growth and development of human organisms. It is required for such fundamental and ubiquitous processes as respiration and protection... (Review)
Review
Copper (Cu) is indispensible for growth and development of human organisms. It is required for such fundamental and ubiquitous processes as respiration and protection against reactive oxygen species. Cu also enables catalytic activity of enzymes that critically contribute to the functional identity of many cells and tissues. Pigmentation, production of norepinephrine by the adrenal gland, the key steps in the formation of connective tissue, neuroendocrine signaling, wound healing - all these processes require Cu and depend on Cu entering the secretory pathway. To reach the Cu-dependent enzymes in a lumen of the trans-Golgi network and various vesicular compartments, Cu undertakes a complex journey crossing the extracellular and intracellular membranes and staying firmly on course while traveling in a cytosol. The proteins that assist Cu in this journey by mediating its entry, distribution, and export, have been identified. The accumulating data also indicate that the current model of cellular Cu homeostasis is still a "skeleton" that has to be fleshed out with many new details. This review summarizes recent data on the mechanisms responsible for Cu transfer to the secretory pathway. The emerging new concepts and gaps in our knowledge are discussed.
Topics: Animals; Biological Transport; Copper; Copper-Transporting ATPases; Homeostasis; Humans; Secretory Pathway
PubMed: 27603756
DOI: 10.1039/c6mt00176a -
Experimental Physiology Mar 2023What is the topic of this review? How the placenta, which transports nutrients and oxygen to the fetus, may alter its support of fetal growth developmentally and with... (Review)
Review
NEW FINDINGS
What is the topic of this review? How the placenta, which transports nutrients and oxygen to the fetus, may alter its support of fetal growth developmentally and with adverse gestational conditions. What advances does it highlight? Placental formation and function alter with the needs of the fetus for substrates for growth during normal gestation and when there is enhanced competition for substrates in species with multiple gestations or adverse gestational environments, and this is mediated by imprinted genes, signalling pathways, mitochondria and fetal sexomes.
ABSTRACT
The placenta is vital for mammalian development and a key determinant of life-long health. It is the interface between the mother and fetus and is responsible for transporting the nutrients and oxygen a fetus needs to develop and grow. Alterations in placental formation and function, therefore, have consequences for fetal growth and birthweight, which in turn determine perinatal survival and risk of non-communicable diseases for the offspring in later postnatal life. However, the placenta is not a static organ. As this review summarizes, research from multiple species has demonstrated that placental formation and function alter developmentally to the needs of the fetus for substrates for growth during normal gestation, as well as when there is greater competition for substrates in polytocous species and monotocous species with multiple gestations. The placenta also adapts in response to the gestational environment, integrating information about the ability of the mother to provide nutrients and oxygen with the needs of the fetus in that prevailing environment. In particular, placental structure (e.g. vascularity, surface area, blood flow, diffusion distance) and transport capacity (e.g. nutrient transporter levels and activity) respond to suboptimal gestational environments, namely malnutrition, obesity, hypoxia and maternal ageing. Mechanisms mediating developmentally and environmentally induced homeostatic responses of the placenta that help support normal fetal growth include imprinted genes, signalling pathways, subcellular constituents and fetal sexomes. Identification of these placental strategies may inform the development of therapies for complicated human pregnancies and advance understanding of the pathways underlying poor fetal outcomes and their consequences for health and disease risk.
Topics: Animals; Pregnancy; Female; Humans; Placenta; Fetal Development; Fetus; Membrane Transport Proteins; Oxygen; Mammals
PubMed: 36484327
DOI: 10.1113/EP090442 -
International Journal of Molecular... Jan 2022Higher concentration of protons in the mitochondrial intermembrane space compared to the matrix results in an electrochemical potential causing the back flux of protons... (Review)
Review
Higher concentration of protons in the mitochondrial intermembrane space compared to the matrix results in an electrochemical potential causing the back flux of protons to the matrix. This proton transport can take place through ATP synthase complex (leading to formation of ATP) or can occur via proton transporters of the mitochondrial carrier superfamily and/or membrane lipids. Some mitochondrial proton transporters, such as uncoupling proteins (UCPs), transport protons as their general regulating function; while others are symporters or antiporters, which use the proton gradient as a driving force to co-transport other substrates across the mitochondrial inner membrane (such as phosphate carrier, a symporter; or aspartate/glutamate transporter, an antiporter). Passage (or leakage) of protons across the inner membrane to matrix from any route other than ATP synthase negatively impacts ATP synthesis. The focus of this review is on regulated proton transport by UCPs. Recent findings on the structure and function of UCPs, and the related research methodologies, are also critically reviewed. Due to structural similarity of members of the mitochondrial carrier superfamily, several of the known structural features are potentially expandable to all members. Overall, this report provides a brief, yet comprehensive, overview of the current knowledge in the field.
Topics: Animals; Gene Expression Regulation; Humans; Ion Transport; Membrane Potential, Mitochondrial; Mitochondria; Mitochondrial Uncoupling Proteins; Models, Molecular; Protein Conformation
PubMed: 35163451
DOI: 10.3390/ijms23031528