Aquaporin-driven hydrogen peroxide transport: a case of molecular mimicry?
Ontology highlight
ABSTRACT:
SUBMITTER: Wragg D
PROVIDER: S-EPMC8341912 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Reactive oxygen species (ROS), particularly hydrogen peroxide (H2O2), cause oxidative cell damage and inhibit sperm function. In most oviparous fishes that spawn in seawater (SW), spermatozoa may be exposed to harmful ROS loads associated with the hyperosmotic stress of axonemal activation and ATP synthesis from mitochondrial oxidative phosphorylation. However, it is not known how marine spermatozoa can cope with the increased ROS levels to maintain flagellar motility. Here, we show that a marine teleost orthologue of human aquaporin-8, termed Aqp8b, is rapidly phosphorylated and inserted into the inner mitochondrial membrane of SW-activated spermatozoa, where it facilitates H2O2 efflux from this compartment. When Aqp8b intracellular trafficking and mitochondrial channel activity are immunologically blocked in activated spermatozoa, ROS levels accumulate in the mitochondria leading to mitochondrial membrane depolarisation, the reduction of ATP production, and the progressive arrest of sperm motility. However, the decreased sperm vitality underlying Aqp8b loss of function is fully reversed in the presence of a mitochondria-targeted antioxidant. These findings reveal a previously unknown detoxification mechanism in spermatozoa under hypertonic conditions, whereby mitochondrial Aqp8b-mediated H2O2 efflux permits fuel production and the maintenance of flagellar motility.
| S-EPMC4293619 | biostudies-literature
Project description:Most breast cancer mortality is due to clinical relapse associated with metastasis. CXCL12/CXCR4-dependent cell migration is a critical process in breast cancer progression; however, its underlying mechanism remains to be elucidated. Here, we show that the water/glycerol channel protein aquaporin-3 (AQP3) is required for CXCL12/CXCR4-dependent breast cancer cell migration through a mechanism involving its hydrogen peroxide (H2O2) transport function. Extracellular H2O2, produced by CXCL12-activated membrane NADPH oxidase 2 (Nox2), was transported into breast cancer cells via AQP3. Transient H2O2 accumulation was observed around the membrane during CXCL12-induced migration, which may be facilitated by the association of AQP3 with Nox2. Intracellular H2O2 then oxidized PTEN and protein tyrosine phosphatase 1B (PTP1B) followed by activation of the Akt pathway. This contributed to directional cell migration. The expression level of AQP3 in breast cancer cells was related to their migration ability both in vitro and in vivo through CXCL12/CXCR4- or H2O2-dependent pathways. Coincidentally, spontaneous metastasis of orthotopic xenografts to the lung was reduced upon AQP3 knockdown. These findings underscore the importance of AQP3-transported H2O2 in CXCL12/CXCR4-dependent signaling and migration in breast cancer cells and suggest that AQP3 has potential as a therapeutic target for breast cancer.
| S-EPMC4800788 | biostudies-literature
Project description:Aquaporin 3 (AQP3), a water/glycerol channel protein, has been found to transport hydrogen peroxide (H2O2). Here, we show that H2O2, imported via AQP3, is involved in nuclear factor-?B (NF-?B) signalling in keratinocytes and in the pathogenesis of psoriasis. IL-23-mediated induction of psoriasis is reduced in AQP3 knockout mice (AQP3(-/-)), and is accompanied by impaired NF-?B activation and intracellular H2O2 accumulation. In primary keratinocyte cultures, cellular import of H2O2 produced by membrane NADPH oxidase 2 (Nox2) in response to TNF-? is facilitated by AQP3 and required for NF-?B activation by regulation of protein phosphatase 2A. As AQP3 associates with Nox2, we propose that this interplay constitutes H2O2-mediated signalling in response to TNF-? stimulation. Collectively, these data indicate that AQP3-facilitated H2O2 transport is required for NF-?B activation in keratinocytes in the development of psoriasis.
| S-EPMC5628617 | biostudies-literature
Project description:Aquaporin-8 (AQP8), a member of the aquaporin family, is strongly expressed in follicular granulosa cells, which could affect the hormone secretion level in females. AQP8, as a membrane protein, could mediate H2O2 into cells, thereby triggering various biological events. The deficiency of Aqp8 increases female fertility, resulting from the decrease in follicular atresia. The low cell death rate is related to the apoptosis of granulosa cells. However, the mechanism by which AQP8 regulates the autophagy of granulosa cells remains unclear. Thus, this study aimed to explore the effect of AQP8 on autophagy in follicular atresia. We found that the expression of the autophagy marker light-chain protein 3 was significantly downregulated in the granulosa cells of Aqp8-knockout (Aqp8 -/- ) mice, compared with wild-type (Aqp8 +/+ ) mice. Immunofluorescence staining and transmission electron microscopic examination indicated that the number of autophagosomes in the granulosa cells of Aqp8 -/- mice decreased. Using a follicular granulosa cell autophagy model, namely a follicular atresia model, we verified that the concentration of H2O2 significantly increased during the autophagy of granulosa cells, consistent with the Aqp8 mRNA level. Intracellular H2O2 accumulation was modulated by endogenous AQP8 expression level, indicating that AQP8-mediated H2O2 was involved in the autophagy of granulosa cells. AQP8 deficiency impaired the elevation of H2O2 concentration through phosphorylated tyrosine activation. In addition, we carried out the analysis of transcriptome sequencing datasets in the ovary and found there were obvious differences in principal components, differentially expressed genes (DEGs) and KEGG pathways, which might be involved in AQP8-regulated follicular atresia. Taken together, these findings indicated that AQP8-mediated H2O2 transport could mediate the autophagy of granulosa cells. AQP8 might be a potential target for diseases related to ovarian insufficiency.
| S-EPMC9445271 | biostudies-literature
Project description:Hydrogen peroxide (H(2)O(2)) produced by cell-surface NADPH Oxidase (Nox) enzymes is emerging as an important signaling molecule for growth, differentiation, and migration processes. However, how cells spatially regulate H(2)O(2) to achieve physiological redox signaling over nonspecific oxidative stress pathways is insufficiently understood. Here we report that the water channel Aquaporin-3 (AQP3) can facilitate the uptake of H(2)O(2) into mammalian cells and mediate downstream intracellular signaling. Molecular imaging with Peroxy Yellow 1 Methyl-Ester (PY1-ME), a new chemoselective fluorescent indicator for H(2)O(2), directly demonstrates that aquaporin isoforms AQP3 and AQP8, but not AQP1, can promote uptake of H(2)O(2) specifically through membranes in mammalian cells. Moreover, we show that intracellular H(2)O(2) accumulation can be modulated up or down based on endogenous AQP3 expression, which in turn can influence downstream cell signaling cascades. Finally, we establish that AQP3 is required for Nox-derived H(2)O(2) signaling upon growth factor stimulation. Taken together, our findings demonstrate that the downstream intracellular effects of H(2)O(2) can be regulated across biological barriers, a discovery that has broad implications for the controlled use of this potentially toxic small molecule for beneficial physiological functions.
| S-EPMC2936599 | biostudies-literature
Project description:Neuromyelitis optica (NMO) is associated with antibodies to aquaporin 4 (AQP4). We hypothesized that antibodies to AQP4 can be triggered by exposure to environmental proteins. We compared human AQP4 to plant and bacterial proteins to investigate the occurrence of significantly similar structures and sequences. High similarity to a known epitope for NMO-IgG, AQP4(207-232), was observed for corn ZmTIP4-1. NMO and non-NMO sera were assessed for reactivity to AQP4(207-232) and the corn peptide. NMO patient serum showed reactivity to both peptides as well as to plant tissue. These findings warrant further investigation into the role of the environment in NMO etiology.
| S-EPMC3682654 | biostudies-literature
Project description:Most anti-cancer agents and radiotherapy exert their therapeutic effects via the production of free radicals. Ferroptosis is a recently described cell death process that is accompanied by iron-dependent lipid peroxidation. Hydrogen peroxide (H2O2) has been reported to induce cell death. However, it remains controversial whether H2O2-induced cell death is ferroptosis. In the present study, we aimed to elucidate the involvement of mitochondria in H2O2-induced ferroptosis and examined the molecules that regulate ferroptosis. We found that one mechanism underlying H2O2-induced cell death is ferroptosis, which occurs soon after H2O2 treatment (within 3 h after H2O2 treatment). We also investigated the involvement of mitochondria in H2O2-induced ferroptosis using mitochondrial DNA-depleted ρ0 cells because ρ0 cells produce more lipid peroxidation, hydroxyl radicals (•OH), and are more sensitive to H2O2 treatment. We found that ρ0 cells contain high Fe2+ levels that lead to •OH production by H2O2. Further, we observed that aquaporin (AQP) 3, 5, and 8 bind nicotinamide-adenine dinucleotide phosphate oxidase 2 and regulate the permeability of extracellular H2O2, thereby contributing to ferroptosis. Additionally, the role of mitochondria in ferroptosis was investigated using mitochondrial transfer in ρ0 cells. When mitochondria were transferred into ρ0 cells, the cells exhibited no sensitivity to H2O2-induced cytotoxicity because of decreased Fe2+ levels. Moreover, mitochondrial transfer upregulated the mitochondrial quality control protein prohibitin 2 (PHB2), which contributes to reduced AQP expression. Our findings also revealed the involvement of AQP and PHB2 in ferroptosis. Our results indicate that H2O2 treatment enhances AQP expression, Fe2+ level, and lipid peroxidation, and decrease mitochondrial function by downregulating PHB2, and thus, is a promising modality for effective cancer treatment.
| S-EPMC7530583 | biostudies-literature
Project description:For efficient removal of intra- and/or extracellular hydrogen peroxide by dismutation to harmless dioxygen and water (2H(2)O(2) → O(2) + 2H(2)O), nature designed three metalloenzyme families that differ in oligomeric organization, monomer architecture as well as active site geometry and catalytic residues. Here we report on the updated reconstruction of the molecular phylogeny of these three gene families. Ubiquitous typical (monofunctional) heme catalases are found in all domains of life showing a high structural conservation. Their evolution was directed from large subunit towards small subunit proteins and further to fused proteins where the catalase fold was retained but lost its original functionality. Bifunctional catalase-peroxidases were at the origin of one of the two main heme peroxidase superfamilies (i.e. peroxidase-catalase superfamily) and constitute a protein family predominantly present among eubacteria and archaea, but two evolutionary branches are also found in the eukaryotic world. Non-heme manganese catalases are a relatively small protein family with very old roots only present among bacteria and archaea. Phylogenetic analyses of the three protein families reveal features typical (i) for the evolution of whole genomes as well as (ii) for specific evolutionary events including horizontal gene transfer, paralog formation and gene fusion. As catalases have reached a striking diversity among prokaryotic and eukaryotic pathogens, understanding their phylogenetic and molecular relationship and function will contribute to drug design for prevention of diseases of humans, animals and plants.
| S-EPMC3523812 | biostudies-literature
Project description:Peroxidases and peroxygenases are promising classes of enzymes for biocatalysis because of their ability to carry out one-electron oxidation reactions and stereoselective oxyfunctionalizations. However, industrial application is limited, as the major drawback is the sensitivity toward the required peroxide substrates. Herein, we report a novel biocatalysis approach to circumvent this shortcoming: in situ production of H2 O2 by dielectric barrier discharge plasma. The discharge plasma can be controlled to produce hydrogen peroxide at desired rates, yielding desired concentrations. Using horseradish peroxidase, it is demonstrated that hydrogen peroxide produced by plasma treatment can drive the enzymatic oxidation of model substrates. Fungal peroxygenase is then employed to convert ethylbenzene to (R)-1-phenylethanol with an ee of >96 % using plasma-generated hydrogen peroxide. As direct treatment of the reaction solution with plasma results in reduced enzyme activity, the use of plasma-treated liquid and protection strategies are investigated to increase total turnover. Technical plasmas present a noninvasive means to drive peroxide-based biotransformations.
| S-EPMC7216967 | biostudies-literature
Project description:Reactive oxygen species (ROS), including H2O2, contribute to oxidative stress and may cause cancer initiation and progression. However, at low concentrations, H2O2 can regulate signaling pathways modulating cell growth, differentiation, and migration. A few mammalian aquaporins (AQPs) facilitate H2O2 diffusion across membranes and participate in tumorigenesis. AQP3 and AQP5 are strongly expressed in cancer tissues and AQP3-mediated H2O2 transport has been related to breast cancer cell migration, but studies with human AQP5 are lacking. Here, we report that, in addition to its established water permeation capacity, human AQP5 facilitates transmembrane H2O2 diffusion and modulates cell growth of AQP5-transformed yeast cells in response to oxidative stress. Mutagenesis studies revealed that residue His173 located in the selective filter is crucial for AQP5 permeability, and interactions with phosphorylated Ser183 may regulate permeation through pore blockage. Moreover, in human pancreatic cancer cells, the measured AQP5-mediated H2O2 influx rate indicates the presence of a highly efficient peroxiporin activity. Cell migration was similarly suppressed by AQP3 or AQP5 gene silencing and could be recovered by external oxidative stimuli. Altogether, these results unveiled a major role for AQP5 in dynamic fine-tuning of the intracellular H2O2 concentration, and consequently in activating signaling networks related to cell survival and cancer progression, highlighting AQP5 as a promising drug target for cancer therapies.
| S-EPMC6678198 | biostudies-literature