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Frontiers in Immunology 2023Nearly 50 ATP-binding cassette (ABC) transporters are encoded by mammalian genomes. These transporters are characterized by conserved nucleotide-binding and hydrolysis... (Review)
Review
Nearly 50 ATP-binding cassette (ABC) transporters are encoded by mammalian genomes. These transporters are characterized by conserved nucleotide-binding and hydrolysis (i.e., ATPase) domains, and power directional transport of diverse substrate classes - ions, small molecule metabolites, xenobiotics, hydrophobic drugs, and even polypeptides - into or out of cells or subcellular organelles. Although immunological functions of ABC transporters are only beginning to be unraveled, emerging literature suggests these proteins have under-appreciated roles in the development and function of T lymphocytes, including many of the key effector, memory and regulatory subsets that arise during responses to infection, inflammation or cancers. One transporter in particular, MDR1 (Multidrug resistance-1; encoded by the locus in humans), has taken center stage as a novel player in immune regulation. Although MDR1 remains widely viewed as a simple drug efflux pump in tumor cells, recent evidence suggests that this transporter fills key endogenous roles in enforcing metabolic fitness of activated CD4 and CD8 T cells. Here, we summarize current understanding of the physiological functions of ABC transporters in immune regulation, with a focus on the anti-oxidant functions of MDR1 that may shape both the magnitude and repertoires of antigen-specific effector and memory T cell compartments. While much remains to be learned about the functions of ABC transporters in immunobiology, it is already clear that they represent fertile new ground, both for the definition of novel immunometabolic pathways, and for the discovery of new drug targets that could be leveraged to optimize immune responses to vaccines and cancer immunotherapies.
Topics: Animals; Humans; Membrane Transport Proteins; ATP-Binding Cassette Transporters; Drug Resistance; Neoplasms; Adenosine Triphosphate; Mammals
PubMed: 38022644
DOI: 10.3389/fimmu.2023.1286696 -
Journal of Molecular Medicine (Berlin,... Jan 2021Mitochondria are recognized as the main source of ATP to meet the energy demands of the cell. ATP production occurs by oxidative phosphorylation when electrons are... (Review)
Review
Mitochondria are recognized as the main source of ATP to meet the energy demands of the cell. ATP production occurs by oxidative phosphorylation when electrons are transported through the electron transport chain (ETC) complexes and develop the proton motive force across the inner mitochondrial membrane that is used for ATP synthesis. Studies since the 1960s have been concentrated on the two models of structural organization of ETC complexes known as "solid-state" and "fluid-state" models. However, advanced new techniques such as blue-native gel electrophoresis, mass spectroscopy, and cryogenic electron microscopy for analysis of macromolecular protein complexes provided new data in favor of the solid-state model. According to this model, individual ETC complexes are assembled into macromolecular structures known as respiratory supercomplexes (SCs). A large number of studies over the last 20 years proposed the potential role of SCs to facilitate substrate channeling, maintain the integrity of individual ETC complexes, reduce electron leakage and production of reactive oxygen species, and prevent excessive and random aggregation of proteins in the inner mitochondrial membrane. However, many other studies have challenged the proposed functional role of SCs. Recently, a third model known as the "plasticity" model was proposed that partly reconciles both "solid-state" and "fluid-state" models. According to the "plasticity" model, respiratory SCs can co-exist with the individual ETC complexes. To date, the physiological role of SCs remains unknown, although several studies using tissue samples of patients or animal/cell models of human diseases revealed an associative link between functional changes and the disintegration of SC assembly. This review summarizes and discusses previous studies on the mechanisms and regulation of SC assembly under physiological and pathological conditions.
Topics: Animals; Cell Respiration; Electron Transport Chain Complex Proteins; Humans; Mitochondria
PubMed: 33201259
DOI: 10.1007/s00109-020-02004-8 -
International Journal of Molecular... Feb 2023Mutations in the receptor expression-enhancing protein 1 gene are associated with hereditary spastic paraplegia type 31 (SPG31), a neurological disorder characterized...
Mutations in the receptor expression-enhancing protein 1 gene are associated with hereditary spastic paraplegia type 31 (SPG31), a neurological disorder characterized by length-dependent degeneration of upper motor neuron axons. Mitochondrial dysfunctions have been observed in patients harboring pathogenic variants in , suggesting a key role of bioenergetics in disease-related manifestations. Nevertheless, the regulation of mitochondrial function in SPG31 remains unclear. To elucidate the pathophysiology underlying REEP1 deficiency, we analyzed in vitro the impact of two different mutations on mitochondrial metabolism. Together with mitochondrial morphology abnormalities, loss-of- expression highlighted a reduced ATP production with increased susceptibility to oxidative stress. Furthermore, to translate these findings from in vitro to preclinical models, we knocked down in zebrafish. Zebrafish larvae showed a significant defect in motor axon outgrowth leading to motor impairment, mitochondrial dysfunction, and reactive oxygen species accumulation. Protective antioxidant agents such as resveratrol rescued free radical overproduction and ameliorated the SPG31 phenotype both in vitro and in vivo. Together, our findings offer new opportunities to counteract neurodegeneration in SPG31.
Topics: Animals; Axons; Membrane Transport Proteins; Mutation; Oxidative Stress; Spastic Paraplegia, Hereditary; Zebrafish; Zebrafish Proteins
PubMed: 36834939
DOI: 10.3390/ijms24043527 -
Cell Reports May 2023The bioenergetic mechanisms by which Mycobacterium tuberculosis survives hypoxia are poorly understood. Current models assume that the bacterium shifts to an alternate...
The bioenergetic mechanisms by which Mycobacterium tuberculosis survives hypoxia are poorly understood. Current models assume that the bacterium shifts to an alternate electron acceptor or fermentation to maintain membrane potential and ATP synthesis. Counterintuitively, we find here that oxygen itself is the principal terminal electron acceptor during hypoxic dormancy. M. tuberculosis can metabolize oxygen efficiently at least two orders of magnitude below the concentration predicted to occur in hypoxic lung granulomas. Despite a difference in apparent affinity for oxygen, both the cytochrome bcc:aa and cytochrome bd oxidase respiratory branches are required for hypoxic respiration. Simultaneous inhibition of both oxidases blocks oxygen consumption, reduces ATP levels, and kills M. tuberculosis under hypoxia. The capacity of mycobacteria to scavenge trace levels of oxygen, coupled with the absence of complex regulatory mechanisms to achieve hierarchal control of the terminal oxidases, may be a key determinant of long-term M. tuberculosis survival in hypoxic lung granulomas.
Topics: Humans; Mycobacterium tuberculosis; Oxygen; Electron Transport Complex IV; Oxidoreductases; Homeostasis; Tuberculosis; Hypoxia; Adenosine Triphosphate; Cytochromes
PubMed: 37115669
DOI: 10.1016/j.celrep.2023.112444 -
Nature Communications Jun 2023Iron is essential to cells as a cofactor in enzymes of respiration and replication, however without correct storage, iron leads to the formation of dangerous oxygen...
Iron is essential to cells as a cofactor in enzymes of respiration and replication, however without correct storage, iron leads to the formation of dangerous oxygen radicals. In yeast and plants, iron is transported into a membrane-bound vacuole by the vacuolar iron transporter (VIT). This transporter is conserved in the apicomplexan family of obligate intracellular parasites, including in Toxoplasma gondii. Here, we assess the role of VIT and iron storage in T. gondii. By deleting VIT, we find a slight growth defect in vitro, and iron hypersensitivity, confirming its essential role in parasite iron detoxification, which can be rescued by scavenging of oxygen radicals. We show VIT expression is regulated by iron at transcript and protein levels, and by altering VIT localization. In the absence of VIT, T. gondii responds by altering expression of iron metabolism genes and by increasing antioxidant protein catalase activity. We also show that iron detoxification has an important role both in parasite survival within macrophages and in virulence in a mouse model. Together, by demonstrating a critical role for VIT during iron detoxification in T. gondii, we reveal the importance of iron storage in the parasite and provide the first insight into the machinery involved.
Topics: Animals; Mice; Toxoplasma; Vacuoles; Reactive Oxygen Species; Membrane Transport Proteins; Parasites; Protozoan Proteins
PubMed: 37339985
DOI: 10.1038/s41467-023-39436-y -
Physiological Reports Jun 2022Pulmonary oxygen uptake ( ) kinetics have been well studied during land-based exercise. However, less is known about kinetics during swimming exercise and comparisons...
Pulmonary oxygen uptake ( ) kinetics have been well studied during land-based exercise. However, less is known about kinetics during swimming exercise and comparisons between strokes is non-existent. We aimed to characterize and compare the kinetics, ventilatory,e and metabolic response to constant velocity moderate-intensity freely breathing front crawl (FC) and breaststroke (BR) swimming in a swimming flume. These two strokes reflect predominantly upper body versus lower body modes of swimming locomotion, respectively. Eight trained swimmers (4 females, 20 ± 1 years, 1.74 ± 0.06 m; 66.8 ± 6.3 kg) attended 5-6 laboratory-based swimming sessions. The first two trials determined FC and BR and the ventilatory threshold (VT), respectively, during progressive intensity swimming to the limit of tolerance. Subsequent trials involved counterbalanced FC and BR transitions from prone floating to constant velocity moderate-intensity swimming at 80% of the velocity at VT (vVT), separated by 30-min recovery. Breath-by-breath changes in pulmonary gas exchange and ventilation were measured continuously using a snorkel and aquatic metabolic cart system. The ventilatory and metabolic responses were similar (p > 0.05) between strokes during maximal velocity swimming, however, vVT and maximal velocity were slower (p < 0.05) during BR . During moderate-intensity swimming, kinetics, ventilatory and metabolic parameters were similar (p > 0.05) between strokes. In conclusion, when breathing ad libitum, kinetics during moderate-intensity constant velocity swimming, and ventilatory and metabolic responses during moderate-intensity and maximal velocity swimming, are similar between FC and BR strokes.
Topics: Female; Humans; Kinetics; Oxygen; Oxygen Consumption; Pulmonary Gas Exchange; Swimming
PubMed: 35757897
DOI: 10.14814/phy2.15361 -
Molecules (Basel, Switzerland) Jan 2022Mitochondrial potassium channels control potassium influx into the mitochondrial matrix and thus regulate mitochondrial membrane potential, volume, respiration, and... (Review)
Review
Mitochondrial potassium channels control potassium influx into the mitochondrial matrix and thus regulate mitochondrial membrane potential, volume, respiration, and synthesis of reactive oxygen species (ROS). It has been found that pharmacological activation of mitochondrial potassium channels during ischemia/reperfusion (I/R) injury activates cytoprotective mechanisms resulting in increased cell survival. In cancer cells, the inhibition of these channels leads to increased cell death. Therefore, mitochondrial potassium channels are intriguing targets for the development of new pharmacological strategies. In most cases, however, the substances that modulate the mitochondrial potassium channels have a few alternative targets in the cell. This may result in unexpected or unwanted effects induced by these compounds. In our review, we briefly present the various classes of mitochondrial potassium (mitoK) channels and describe the chemical compounds that modulate their activity. We also describe examples of the multidirectional activity of the activators and inhibitors of mitochondrial potassium channels.
Topics: Adenosine Triphosphate; Animals; Calcium; Humans; Ion Channel Gating; Mitochondrial Membrane Transport Proteins; Potassium; Potassium Channel Blockers; Potassium Channels
PubMed: 35011530
DOI: 10.3390/molecules27010299 -
Biochimica Et Biophysica Acta.... May 2021Cytochrome bf (cytbf) lies at the heart of the light-dependent reactions of oxygenic photosynthesis, where it serves as a link between photosystem II (PSII) and... (Review)
Review
Cytochrome bf (cytbf) lies at the heart of the light-dependent reactions of oxygenic photosynthesis, where it serves as a link between photosystem II (PSII) and photosystem I (PSI) through the oxidation and reduction of the electron carriers plastoquinol (PQH) and plastocyanin (Pc). A mechanism of electron bifurcation, known as the Q-cycle, couples electron transfer to the generation of a transmembrane proton gradient for ATP synthesis. Cytbf catalyses the rate-limiting step in linear electron transfer (LET), is pivotal for cyclic electron transfer (CET) and plays a key role as a redox-sensing hub involved in the regulation of light-harvesting, electron transfer and photosynthetic gene expression. Together, these characteristics make cytbf a judicious target for genetic manipulation to enhance photosynthetic yield, a strategy which already shows promise. In this review we will outline the structure and function of cytbf with a particular focus on new insights provided by the recent high-resolution map of the complex from Spinach.
Topics: Cell Respiration; Cytochrome b6f Complex; Electron Transport; Electrons; Photosynthesis
PubMed: 33460588
DOI: 10.1016/j.bbabio.2021.148380 -
Plant Signaling & Behavior Dec 2020The oxygen-evolving complex is integrated into photosystem (PSII). An essential part of oxygenic photosynthetic apparatus, embedded in the thylakoid membrane of... (Review)
Review
The oxygen-evolving complex is integrated into photosystem (PSII). An essential part of oxygenic photosynthetic apparatus, embedded in the thylakoid membrane of chloroplasts. The OEC is a super catalyst to split water into molecular oxygen in the presence of light. The OEC consist of four Mn atoms, one Ca atom and five oxygen atoms (CaMnO) and this cluster is maintained by its surrounding proteins ., PsbQ, PsbP, PsbO, PsbR. The function of this super catalyst with a high turnover frequency of 500 s in standard condition. Chlorophyll a fluorescence (OJIP transients) are used to understand structural and functional cohesion of photosynthetic apparatus. A further K-peak in OJIP curve reflects damage at the OEC donor site in response to salinity, drought, and high temperature. The decline in performance indices (PI, SFI) also revealed structural damage of photosynthetic apparatus that leads to disruption of electron transport rate under abiotic conditions. This review discusses the structural and function cohesion of the OEC in plant against variable abiotic conditions.
Topics: Catalysis; Chlorophyll A; Oxygen; Photosystem II Protein Complex; Stress, Physiological; Thylakoids
PubMed: 32970515
DOI: 10.1080/15592324.2020.1824721 -
ELife May 2023Mitochondrial biogenesis requires the import of >1,000 mitochondrial preproteins from the cytosol. Most studies on mitochondrial protein import are focused on the core...
Mitochondrial biogenesis requires the import of >1,000 mitochondrial preproteins from the cytosol. Most studies on mitochondrial protein import are focused on the core import machinery. Whether and how the biophysical properties of substrate preproteins affect overall import efficiency is underexplored. Here, we show that protein traffic into mitochondria can be disrupted by amino acid substitutions in a single substrate preprotein. Pathogenic missense mutations in ADP/ATP translocase 1 (ANT1), and its yeast homolog ADP/ATP carrier 2 (Aac2), cause the protein to accumulate along the protein import pathway, thereby obstructing general protein translocation into mitochondria. This impairs mitochondrial respiration, cytosolic proteostasis, and cell viability independent of ANT1's nucleotide transport activity. The mutations act synergistically, as double mutant Aac2/ANT1 causes severe clogging primarily at the translocase of the outer membrane (TOM) complex. This confers extreme toxicity in yeast. In mice, expression of a super-clogger ANT1 variant led to neurodegeneration and an age-dependent dominant myopathy that phenocopy ANT1-induced human disease, suggesting clogging as a mechanism of disease. More broadly, this work implies the existence of uncharacterized amino acid requirements for mitochondrial carrier proteins to avoid clogging and subsequent disease.
Topics: Animals; Humans; Mice; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Mitochondria; Mitochondrial ADP, ATP Translocases; Carrier Proteins; Protein Transport; Mitochondrial Proteins; Mitochondrial Membrane Transport Proteins
PubMed: 37129366
DOI: 10.7554/eLife.84330