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Physiological Reviews Oct 2015Aquaporins are membrane channels that facilitate the transport of water and small neutral molecules across biological membranes of most living organisms. In plants,... (Review)
Review
Aquaporins are membrane channels that facilitate the transport of water and small neutral molecules across biological membranes of most living organisms. In plants, aquaporins occur as multiple isoforms reflecting a high diversity of cellular localizations, transport selectivity, and regulation properties. Plant aquaporins are localized in the plasma membrane, endoplasmic reticulum, vacuoles, plastids and, in some species, in membrane compartments interacting with symbiotic organisms. Plant aquaporins can transport various physiological substrates in addition to water. Of particular relevance for plants is the transport of dissolved gases such as carbon dioxide and ammonia or metalloids such as boron and silicon. Structure-function studies are developed to address the molecular and cellular mechanisms of plant aquaporin gating and subcellular trafficking. Phosphorylation plays a central role in these two processes. These mechanisms allow aquaporin regulation in response to signaling intermediates such as cytosolic pH and calcium, and reactive oxygen species. Combined genetic and physiological approaches are now integrating this knowledge, showing that aquaporins play key roles in hydraulic regulation in roots and leaves, during drought but also in response to stimuli as diverse as flooding, nutrient availability, temperature, or light. A general hydraulic control of plant tissue expansion by aquaporins is emerging, and their role in key developmental processes (seed germination, emergence of lateral roots) has been established. Plants with genetically altered aquaporin functions are now tested for their ability to improve plant tolerance to stresses. In conclusion, research on aquaporins delineates ever expanding fields in plant integrative biology thereby establishing their crucial role in plants.
Topics: Animals; Aquaporins; Biological Transport; Humans; Hydrogen-Ion Concentration; Plants; Stress, Physiological
PubMed: 26336033
DOI: 10.1152/physrev.00008.2015 -
Cell Metabolism Mar 2021The metabolic rewiring of cardiomyocytes is a widely accepted hallmark of heart failure (HF). These metabolic changes include a decrease in mitochondrial pyruvate...
The metabolic rewiring of cardiomyocytes is a widely accepted hallmark of heart failure (HF). These metabolic changes include a decrease in mitochondrial pyruvate oxidation and an increased export of lactate. We identify the mitochondrial pyruvate carrier (MPC) and the cellular lactate exporter monocarboxylate transporter 4 (MCT4) as pivotal nodes in this metabolic axis. We observed that cardiac assist device-induced myocardial recovery in chronic HF patients was coincident with increased myocardial expression of the MPC. Moreover, the genetic ablation of the MPC in cultured cardiomyocytes and in adult murine hearts was sufficient to induce hypertrophy and HF. Conversely, MPC overexpression attenuated drug-induced hypertrophy in a cell-autonomous manner. We also introduced a novel, highly potent MCT4 inhibitor that mitigated hypertrophy in cultured cardiomyocytes and in mice. Together, we find that alteration of the pyruvate-lactate axis is a fundamental and early feature of cardiac hypertrophy and failure.
Topics: Animals; Anion Transport Proteins; Cardiomegaly; Heart Failure; Heart-Assist Devices; Humans; Lactic Acid; Membrane Potential, Mitochondrial; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Mitochondrial Membrane Transport Proteins; Monocarboxylic Acid Transporters; Muscle Proteins; Myocytes, Cardiac; Pyruvic Acid; RNA Interference; RNA, Small Interfering; Reactive Oxygen Species; Ventricular Function, Left
PubMed: 33333007
DOI: 10.1016/j.cmet.2020.12.003 -
Current Biology : CB Nov 2017Mitochondria are best known for their role in the generation of ATP by aerobic respiration. Yet, research in the past half century has shown that they perform a much... (Review)
Review
Mitochondria are best known for their role in the generation of ATP by aerobic respiration. Yet, research in the past half century has shown that they perform a much larger suite of functions and that these functions can vary substantially among diverse eukaryotic lineages. Despite this diversity, all mitochondria derive from a common ancestral organelle that originated from the integration of an endosymbiotic alphaproteobacterium into a host cell related to Asgard Archaea. The transition from endosymbiotic bacterium to permanent organelle entailed a massive number of evolutionary changes including the origins of hundreds of new genes and a protein import system, insertion of membrane transporters, integration of metabolism and reproduction, genome reduction, endosymbiotic gene transfer, lateral gene transfer and the retargeting of proteins. These changes occurred incrementally as the endosymbiont and the host became integrated. Although many insights into this transition have been gained, controversy persists regarding the nature of the original endosymbiont, its initial interactions with the host and the timing of its integration relative to the origin of other features of eukaryote cells. Since the establishment of the organelle, proteins have been gained, lost, transferred and retargeted as mitochondria have specialized into the spectrum of functional types seen across the eukaryotic tree of life.
Topics: Adenosine Triphosphate; Alphaproteobacteria; Biological Evolution; Eukaryotic Cells; Genome, Mitochondrial; Membrane Transport Proteins; Mitochondria; Protein Transport; Symbiosis
PubMed: 29112874
DOI: 10.1016/j.cub.2017.09.015 -
International Journal of Molecular... Jul 2019The mammalian mitochondrial electron transport chain (ETC) includes complexes I‑IV, as well as the electron transporters ubiquinone and cytochrome c. There are two...
The mammalian mitochondrial electron transport chain (ETC) includes complexes I‑IV, as well as the electron transporters ubiquinone and cytochrome c. There are two electron transport pathways in the ETC: Complex I/III/IV, with NADH as the substrate and complex II/III/IV, with succinic acid as the substrate. The electron flow is coupled with the generation of a proton gradient across the inner membrane and the energy accumulated in the proton gradient is used by complex V (ATP synthase) to produce ATP. The first part of this review briefly introduces the structure and function of complexes I‑IV and ATP synthase, including the specific electron transfer process in each complex. Some electrons are directly transferred to O2 to generate reactive oxygen species (ROS) in the ETC. The second part of this review discusses the sites of ROS generation in each ETC complex, including sites IF and IQ in complex I, site IIF in complex II and site IIIQo in complex III, and the physiological and pathological regulation of ROS. As signaling molecules, ROS play an important role in cell proliferation, hypoxia adaptation and cell fate determination, but excessive ROS can cause irreversible cell damage and even cell death. The occurrence and development of a number of diseases are closely related to ROS overproduction. Finally, proton leak and uncoupling proteins (UCPS) are discussed. Proton leak consists of basal proton leak and induced proton leak. Induced proton leak is precisely regulated and induced by UCPs. A total of five UCPs (UCP1‑5) have been identified in mammalian cells. UCP1 mainly plays a role in the maintenance of body temperature in a cold environment through non‑shivering thermogenesis. The core role of UCP2‑5 is to reduce oxidative stress under certain conditions, therefore exerting cytoprotective effects. All diseases involving oxidative stress are associated with UCPs.
Topics: Animals; Cell Hypoxia; Cell Proliferation; Electron Transport Chain Complex Proteins; Humans; Mitochondria; Mitochondrial Uncoupling Proteins; Oxidative Stress; Reactive Oxygen Species; Signal Transduction; Thermogenesis
PubMed: 31115493
DOI: 10.3892/ijmm.2019.4188 -
Cell Metabolism Apr 2020NADH provides electrons for aerobic ATP production. In cells deprived of oxygen or with impaired electron transport chain activity, NADH accumulation can be toxic. To...
NADH provides electrons for aerobic ATP production. In cells deprived of oxygen or with impaired electron transport chain activity, NADH accumulation can be toxic. To minimize such toxicity, elevated NADH inhibits the classical NADH-producing pathways: glucose, glutamine, and fat oxidation. Here, through deuterium-tracing studies in cultured cells and mice, we show that folate-dependent serine catabolism also produces substantial NADH. Strikingly, when respiration is impaired, serine catabolism through methylene tetrahydrofolate dehydrogenase (MTHFD2) becomes a major NADH source. In cells whose respiration is slowed by hypoxia, metformin, or genetic lesions, mitochondrial serine catabolism inhibition partially normalizes NADH levels and facilitates cell growth. In mice with engineered mitochondrial complex I deficiency (NDUSF4-/-), serine's contribution to NADH is elevated, and progression of spasticity is modestly slowed by pharmacological blockade of serine degradation. Thus, when respiration is impaired, serine catabolism contributes to toxic NADH accumulation.
Topics: Animals; Cell Hypoxia; Cell Line; Humans; Mice; Mice, Inbred C57BL; Mice, Nude; Mitochondria; NAD; Oxygen; Serine
PubMed: 32187526
DOI: 10.1016/j.cmet.2020.02.017 -
Nature Dec 2020Mitochondria require nicotinamide adenine dinucleotide (NAD) to carry out the fundamental processes that fuel respiration and mediate cellular energy transduction....
Mitochondria require nicotinamide adenine dinucleotide (NAD) to carry out the fundamental processes that fuel respiration and mediate cellular energy transduction. Mitochondrial NAD transporters have been identified in yeast and plants, but their existence in mammals remains controversial. Here we demonstrate that mammalian mitochondria can take up intact NAD, and identify SLC25A51 (also known as MCART1)-an essential mitochondrial protein of previously unknown function-as a mammalian mitochondrial NAD transporter. Loss of SLC25A51 decreases mitochondrial-but not whole-cell-NAD content, impairs mitochondrial respiration, and blocks the uptake of NAD into isolated mitochondria. Conversely, overexpression of SLC25A51 or SLC25A52 (a nearly identical paralogue of SLC25A51) increases mitochondrial NAD levels and restores NAD uptake into yeast mitochondria lacking endogenous NAD transporters. Together, these findings identify SLC25A51 as a mammalian transporter capable of importing NAD into mitochondria.
Topics: Animals; Biological Transport; Cell Line; Cell Respiration; Genetic Complementation Test; Humans; Mice; Mitochondria; Mitochondrial Proteins; NAD; Nucleotide Transport Proteins; Organic Cation Transport Proteins; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 32906142
DOI: 10.1038/s41586-020-2741-7 -
Oxidative Medicine and Cellular... 2018
Topics: Alzheimer Disease; Biological Transport; Cardiovascular Diseases; Humans; Membrane Transport Proteins; Oxidative Stress; Reactive Nitrogen Species; Reactive Oxygen Species
PubMed: 30008987
DOI: 10.1155/2018/9625213 -
Science Translational Medicine Jun 2016α-Synuclein accumulation and mitochondrial dysfunction have both been strongly implicated in the pathogenesis of Parkinson's disease (PD), and the two appear to be...
α-Synuclein accumulation and mitochondrial dysfunction have both been strongly implicated in the pathogenesis of Parkinson's disease (PD), and the two appear to be related. Mitochondrial dysfunction leads to accumulation and oligomerization of α-synuclein, and increased levels of α-synuclein cause mitochondrial impairment, but the basis for this bidirectional interaction remains obscure. We now report that certain posttranslationally modified species of α-synuclein bind with high affinity to the TOM20 (translocase of the outer membrane 20) presequence receptor of the mitochondrial protein import machinery. This binding prevented the interaction of TOM20 with its co-receptor, TOM22, and impaired mitochondrial protein import. Consequently, there were deficient mitochondrial respiration, enhanced production of reactive oxygen species, and loss of mitochondrial membrane potential. Examination of postmortem brain tissue from PD patients revealed an aberrant α-synuclein-TOM20 interaction in nigrostriatal dopaminergic neurons that was associated with loss of imported mitochondrial proteins, thereby confirming this pathogenic process in the human disease. Modest knockdown of endogenous α-synuclein was sufficient to maintain mitochondrial protein import in an in vivo model of PD. Furthermore, in in vitro systems, overexpression of TOM20 or a mitochondrial targeting signal peptide had beneficial effects and preserved mitochondrial protein import. This study characterizes a pathogenic mechanism in PD, identifies toxic species of wild-type α-synuclein, and reveals potential new therapeutic strategies for neuroprotection.
Topics: Animals; Membrane Transport Proteins; Mitochondria; Mitochondrial Precursor Protein Import Complex Proteins; Mitochondrial Proteins; Parkinson Disease; Protein Binding; Protein Transport; Rats; Rats, Mutant Strains; Receptors, Cell Surface; Receptors, Cytoplasmic and Nuclear; alpha-Synuclein
PubMed: 27280685
DOI: 10.1126/scitranslmed.aaf3634 -
Protein & Cell May 2020Respirasome, as a vital part of the oxidative phosphorylation system, undertakes the task of transferring electrons from the electron donors to oxygen and produces a... (Review)
Review
Respirasome, as a vital part of the oxidative phosphorylation system, undertakes the task of transferring electrons from the electron donors to oxygen and produces a proton concentration gradient across the inner mitochondrial membrane through the coupled translocation of protons. Copious research has been carried out on this lynchpin of respiration. From the discovery of individual respiratory complexes to the report of the high-resolution structure of mammalian respiratory supercomplex IIIIIV, scientists have gradually uncovered the mysterious veil of the electron transport chain (ETC). With the discovery of the mammalian respiratory mega complex IIIIIV, a new perspective emerges in the research field of the ETC. Behind these advances glitters the light of the revolution in both theory and technology. Here, we give a short review about how scientists 'see' the structure and the mechanism of respirasome from the macroscopic scale to the atomic scale during the past decades.
Topics: Animals; Cell Respiration; Cryoelectron Microscopy; Electron Transport; Electron Transport Chain Complex Proteins; Humans; Mitochondrial Membranes; Models, Molecular; Oxidative Phosphorylation; Protons
PubMed: 31919741
DOI: 10.1007/s13238-019-00681-x -
Nature Metabolism Nov 2023T cell activation is associated with a profound and rapid metabolic response to meet increased energy demands for cell division, differentiation and development of...
T cell activation is associated with a profound and rapid metabolic response to meet increased energy demands for cell division, differentiation and development of effector function. Glucose uptake and engagement of the glycolytic pathway are major checkpoints for this event. Here we show that the low-affinity, concentration-dependent glucose transporter 2 (Glut2) regulates the development of CD8 T cell effector responses in mice by promoting glucose uptake, glycolysis and glucose storage. Expression of Glut2 is modulated by environmental factors including glucose and oxygen availability and extracellular acidification. Glut2 is highly expressed by circulating, recently primed T cells, allowing efficient glucose uptake and storage. In glucose-deprived inflammatory environments, Glut2 becomes downregulated, thus preventing passive loss of intracellular glucose. Mechanistically, Glut2 expression is regulated by a combination of molecular interactions involving hypoxia-inducible factor-1 alpha, galectin-9 and stomatin. Finally, we show that human T cells also rely on this glucose transporter, thus providing a potential target for therapeutic immunomodulation.
Topics: Mice; Humans; Animals; Glucose; Biological Transport; Glucose Transport Proteins, Facilitative; Cell Differentiation; CD8-Positive T-Lymphocytes
PubMed: 37884694
DOI: 10.1038/s42255-023-00913-9