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1.
Int J Biol Sci ; 20(11): 4222-4237, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39247821

RESUMO

Aortic dissection (AD), caused by tearing of the intima and avulsion of the aortic media, is a severe threat to patient life and organ function. Iron is closely related to dissection formation and organ injury, but the mechanism of iron ion transport disorder in endothelial cells (ECs) remains unclear. We identified the characteristic EC of dissection with iron overload by single-cell RNA sequencing data. After intersecting iron homeostasis and differentially expressed genes, it was found that hypoxia-inducible factor-1α (HIF-1α) and divalent metal transporter 1 (DMT1) are key genes for iron ion disorder. Subsequently, IL-6R was identified as an essential reason for the JAK-STAT activation, a classical iron regulation pathway, through further intersection and validation. In in vivo and in vitro, both high IL-6 receptor expression and elevated IL-6 levels promote JAK1-STAT3 phosphorylation, leading to increased HIF-1α protein levels. Elevated HIF-1α binds explicitly to the 5'-UTR sequence of the DMT1 gene and transcriptionally promotes DMT1 expression, thereby increasing Fe2+ accumulation and endoplasmic reticulum stress (ERS). Blocking IL-6R and free iron with deferoxamine and tocilizumab significantly prolonged survival and reduced aortic and organ damage in dissection mice. A comparison of perioperative data between AD patients and others revealed that high free iron, IL-6, and ERS levels are characteristics of AD patients and are correlated with prognosis. In conclusion, activated IL-6/JAK1/STAT3 signaling axis up-regulates DMT1 expression by increasing HIF-1α, thereby increasing intracellular Fe2+ accumulation and tissue injury, which suggests a potential therapeutic target for AD.


Assuntos
Dissecção Aórtica , Proteínas de Transporte de Cátions , Células Endoteliais , Interleucina-6 , Sobrecarga de Ferro , Transdução de Sinais , Animais , Interleucina-6/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Proteínas de Transporte de Cátions/genética , Camundongos , Células Endoteliais/metabolismo , Humanos , Dissecção Aórtica/metabolismo , Sobrecarga de Ferro/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Fator de Transcrição STAT3/metabolismo , Regulação para Cima , Ferro/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética
2.
Proc Natl Acad Sci U S A ; 121(37): e2407455121, 2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-39240971

RESUMO

Succinic acid (SA), a dicarboxylic acid of industrial importance, can be efficiently produced by metabolically engineered Mannheimia succiniciproducens. Although the importance of magnesium (Mg2+) ion on SA production has been evident from our previous studies, the role of Mg2+ ion remains largely unexplored. In this study, we investigated the impact of Mg2+ ion on SA production and developed a hyper-SA producing strain of M. succiniciproducens by reconstructing the Mg2+ ion transport system. To achieve this, optimal alkaline neutralizer comprising Mg2+ ion was developed and the physiological effect of Mg2+ ion was analyzed. Subsequently, the Mg2+ ion transport system was reconstructed by introducing an efficient Mg2+ ion transporter from Salmonella enterica. A high-inoculum fed-batch fermentation of the final engineered strain produced 152.23 ± 0.99 g/L of SA, with a maximum productivity of 39.64 ± 0.69 g/L/h. These findings highlight the importance of Mg2+ ions and transportation system optimization in succinic acid production by M. succiniciproducens.


Assuntos
Fermentação , Magnésio , Mannheimia , Ácido Succínico , Ácido Succínico/metabolismo , Magnésio/metabolismo , Mannheimia/metabolismo , Mannheimia/genética , Engenharia Metabólica/métodos , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/genética , Proteínas de Transporte de Cátions/metabolismo , Proteínas de Transporte de Cátions/genética
3.
Cell Death Dis ; 15(9): 656, 2024 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-39242581

RESUMO

Thyroid cancer is the most frequently observed endocrine-related malignancy among which anaplastic thyroid cancer (ATC) is the most fatal subtype. The synthesis of protein is active to satisfy the rapid growth of ATC tumor, but the mechanisms regulating protein synthesis are still unknown. Our research revealed that kinetochore protein NUF2 played an essential role in protein synthesis and drove the progression of ATC. The prognosis of patients with thyroid carcinoma was positively correlated with high NUF2 expression. Depletion of NUF2 in ATC cells notably inhibited the proliferation and induced apoptosis, while overexpression of NUF2 facilitated ATC cell viability and colony formation. Deletion of NUF2 significantly suppressed the growth and metastasis of ATC in vivo. Notably, knockdown of NUF2 epigenetically inhibited the expression of magnesium transporters through reducing the abundance of H3K4me3 at promoters, thereby reduced intracellular Mg2+ concentration. Furthermore, we found the deletion of NUF2 or magnesium transporters significantly inhibited the protein synthesis mediated by the PI3K/Akt/mTOR pathway. In conclusion, NUF2 functions as an emerging regulator for protein synthesis by maintaining the homeostasis of intracellular Mg2+, which finally drives ATC progression.


Assuntos
Progressão da Doença , Homeostase , Magnésio , Carcinoma Anaplásico da Tireoide , Animais , Feminino , Humanos , Camundongos , Apoptose , Proteínas de Transporte de Cátions/metabolismo , Proteínas de Transporte de Cátions/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Magnésio/metabolismo , Camundongos Nus , Biossíntese de Proteínas , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Carcinoma Anaplásico da Tireoide/metabolismo , Carcinoma Anaplásico da Tireoide/patologia , Carcinoma Anaplásico da Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/genética , Serina-Treonina Quinases TOR/metabolismo
4.
Int J Mol Sci ; 25(17)2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-39273585

RESUMO

Neonatal iron deficiency anemia is prevalent among domestic pigs but does not occur in the offspring of wild boar. The main causes of this disorder in piglets of modern pig breeds are paucity of hepatic iron stores, high birth weight, and rapid growth. Replenishment of fetal iron stores is a direct result of iron transfer efficiency across the placenta. In this study, we attempted to investigate the molecular potential of iron transfer across the placenta as a possible cause of differences between wild boar and Polish Large White (PLW) offspring. Furthermore, by analyzing placentas from PLW gilts that had litters of different sizes, we aimed to elucidate the impact of the number of fetuses on placental ability to transport iron. Using RNA sequencing, we examined the expression of iron-related genes in the placentas from wild boar and PLW gilts. We did not reveal significant differences in the expression of major iron transporters among all analyzed placentas. However, in wild boar placentas, we found higher expression of copper-dependent ferroxidases such as ceruloplasmin, zyklopen, and hephaestin, which facilitate iron export to the fetal circulation. We also determined a close co-localization of ceruloplasmin and zyklopen with ferroportin, the only iron exporter.


Assuntos
Ferro , Tamanho da Ninhada de Vivíparos , Placenta , Sus scrofa , Animais , Feminino , Placenta/metabolismo , Ferro/metabolismo , Gravidez , Sus scrofa/metabolismo , Sus scrofa/genética , Suínos , Ceruloplasmina/metabolismo , Ceruloplasmina/genética , Proteínas de Transporte de Cátions/metabolismo , Proteínas de Transporte de Cátions/genética , Transporte Biológico
5.
Int J Mol Sci ; 25(17)2024 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-39273097

RESUMO

Iron is a vital element involved in a plethora of metabolic activities. Mammalian systemic iron homeostasis is mainly modulated by hepcidin, the synthesis of which is regulated by a number of proteins, including the hemochromatosis-associated proteins Hfe and Transferrin Receptor 2 (TfR2). Macrophages play versatile functions in iron homeostasis by storing iron derived from the catabolism of erythrocytes and supplying iron required for erythropoiesis. The absence of Hfe in macrophages causes a mild iron deficiency in aged mice and leads to an overproduction of the iron exporter Ferroportin 1 (Fpn1). Conversely, TfR2 gene silencing in macrophages does not influence systemic iron metabolism but decreases transcription of the macrophage Fpn1 in adult mice and modulates their immune response. This study investigated cellular and systemic iron metabolism in adult and aged male mice with macrophage-specific Hfe and TfR2 silencing (double knock-out, DKO). Serum iron parameters were significantly modified in aged animals, and significant differences were found in hepatic hepcidin transcription at both ages. Interestingly, splenic iron content was low in adult DKOs and splenic Fpn1 transcription was significantly increased in DKO animals at both ages, while the protein amount does not reflect the transcriptional trend. Additionally, DKO macrophages were isolated from mice bone marrow (BMDMs) and showed significant variations in the transcription of iron genes and protein amounts in targeted mice compared to controls. Specifically, Tranferrin Receptor 1 (TfR1) increased in DKO adult mice BMDMs, while the opposite is observed in the cells of aged DKO mice. Fpn1 transcript was significantly decreased in the BMDMs of adult DKO mice, while the protein was reduced at both ages. Lastly, a significant increase in Erythropoietin production was evidenced in aged DKO mice. Overall, our study reveals that Hfe and TfR2 in macrophages regulate hepatic Hepc production and affect iron homeostasis in the spleen and BMDMs, leading to an iron deficiency in aged animals that impairs their erythropoiesis.


Assuntos
Proteína da Hemocromatose , Ferro , Macrófagos , Camundongos Knockout , Receptores da Transferrina , Baço , Animais , Receptores da Transferrina/metabolismo , Receptores da Transferrina/genética , Baço/metabolismo , Ferro/metabolismo , Macrófagos/metabolismo , Camundongos , Masculino , Proteína da Hemocromatose/genética , Proteína da Hemocromatose/metabolismo , Medula Óssea/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Proteínas de Transporte de Cátions/genética , Hepcidinas/metabolismo , Hepcidinas/genética , Camundongos Endogâmicos C57BL , Homeostase , Fígado/metabolismo
6.
Int J Mol Sci ; 25(17)2024 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-39273144

RESUMO

Type 2 diabetes mellitus (T2DM) is a complex chronic disease characterized by decreased insulin secretion and the development of insulin resistance. Previous genome-wide association studies demonstrated that single-nucleotide polymorphisms (SNPs) present in genes coding for ion channels involved in insulin secretion increase the risk of developing this disease. We determined the association of 16 SNPs found in CACNA1D, KCNQ1, KCNJ11, and CACNA1E genes and the increased probability of developing T2DM. In this work, we performed a case-control study in 301 Mexican adults, including 201 cases with diabetes and 100 controls without diabetes. Our findings indicate a moderate association between T2DM and the C allele, and the C/C genotype of rs312480 within CACNA1D. The CAG haplotype surprisingly showed a protective effect, whereas the CAC and CGG haplotypes have a strong association with T2DM. The C allele and C/C genotype of rs5219 were significantly associated with diabetes. Also, an association was observed between diabetes and the A allele and the A/A genotype of rs3753737 and rs175338 in CACNA1E. The TGG and CGA haplotypes were also found to be significantly associated. The findings of this study indicate that the SNPs examined could serve as a potential diagnostic tool and contribute to the susceptibility of the Mexican population to this disease.


Assuntos
Canais de Cálcio Tipo L , Diabetes Mellitus Tipo 2 , Predisposição Genética para Doença , Canal de Potássio KCNQ1 , Polimorfismo de Nucleotídeo Único , Canais de Potássio Corretores do Fluxo de Internalização , Humanos , Diabetes Mellitus Tipo 2/genética , Canais de Cálcio Tipo L/genética , Canal de Potássio KCNQ1/genética , Feminino , Masculino , Canais de Potássio Corretores do Fluxo de Internalização/genética , Pessoa de Meia-Idade , Estudos de Casos e Controles , Adulto , Haplótipos , Canais de Cálcio Tipo R/genética , Alelos , México , Idoso , Estudos de Associação Genética , Genótipo , Frequência do Gene , Proteínas de Transporte de Cátions
7.
BMC Genomics ; 25(1): 836, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-39237905

RESUMO

BACKGROUND: The KT/HAK/KUP is the largest K+ transporter family in plants, playing crucial roles in K+ absorption, transport, and defense against environmental stress. Sweet watermelon is an economically significant horticultural crop belonging to the genus Citrullus, with a high demand for K+ during its growth process. However, a comprehensive analysis of the KT/HAK/KUP gene family in watermelon has not been reported. RESULTS: 14 KT/HAK/KUP genes were identified in the genomes of each of seven Citrullus species. These KT/HAK/KUPs in watermelon were unevenly distributed across seven chromosomes. Segmental duplication is the primary driving force behind the expansion of the KT/HAK/KUP family, subjected to purifying selection during domestication (Ka/Ks < 1), and all KT/HAK/KUPs exhibit conserved motifs and could be phylogenetically classified into four groups. The promoters of KT/HAK/KUPs contain numerous cis-regulatory elements related to plant growth and development, phytohormone response, and stress response. Under K+ deficiency, the growth of watermelon seedlings was significantly inhibited, with cultivated watermelon experiencing greater impacts (canopy width, redox enzyme activity) compared to the wild type. All KT/HAK/KUPs in C. lanatus and C. amarus exhibit specific expression responses to K+-deficiency and drought stress by qRT-PCR. Notably, ClG42_07g0120700/CaPI482276_07g014010 were predominantly expressed in roots and were further induced by K+-deficiency and drought stress. Additionally, the K+ transport capacity of ClG42_07g0120700 under low K+ stress was confirmed by yeast functional complementation assay. CONCLUSIONS: KT/HAK/KUP genes in watermelon were systematically identified and analyzed at the pangenome level and provide a foundation for understanding the classification and functions of the KT/HAK/KUPs in watermelon plants.


Assuntos
Citrullus , Secas , Filogenia , Proteínas de Plantas , Estresse Fisiológico , Citrullus/genética , Citrullus/metabolismo , Citrullus/crescimento & desenvolvimento , Estresse Fisiológico/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Potássio/metabolismo , Regulação da Expressão Gênica de Plantas , Genoma de Planta , Família Multigênica , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Deficiência de Potássio/genética , Deficiência de Potássio/metabolismo , Regiões Promotoras Genéticas
8.
CNS Neurosci Ther ; 30(9): e70018, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39252474

RESUMO

OBJECTIVE: Nowadays, the prevalence of cognitive impairment in women has gradually increased, especially in postmenopausal women. There were few studies on the mechanistic effects of iron exposure on neurotoxicity in postmenopausal women. The aim of this study is to investigate the effect of iron accumulation on cognitive ability in ovariectomized mice and its possible mechanism and to provide a scientific basis for the prevention of cognitive dysfunction in postmenopausal women. METHODS: Female C57BL/6N ovariectomized model mice were induced with ferric citrate (FAC). The mice were randomly divided into 5 groups: control, sham, ovariectomized (Ovx), Ovx + 50 mg/kg FAC (Ovx + l), and Ovx + 100 mg/kg FAC (Ovx + h). The impact of motor and cognitive function was verified by a series of behavioral tests. The levels of serum iron parameters, malondialdehyde, and superoxide dismutase were measured. The ultrastructure of mice hippocampal microglia was imaged by transmission electron microscopy. The differential expression of hippocampal proteins was analyzed by Tandem Mass Tag labeling. RESULTS: Movement and cognitive function in Ovx + l/Ovx + h mice were significantly decreased compared to control and Sham mice. Then, iron exposure caused histopathological changes in the hippocampus of mice. In addition, proteomic analysis revealed that 29/27/41 proteins were differentially expressed in the hippocampus when compared by Ovx vs. Sham, Ovx + l vs. Ovx, as well as Ovx + h vs. Ovx + l groups, respectively. Moreover, transferrin receptor protein (TFR1) and divalent metal transporter 1 (DMT1) protein expression were significantly increased in the iron accumulation mice model with ovariectomy. CONCLUSION: Iron exposure could cause histopathological damage in the hippocampus of ovariectomised mice and, by altering hippocampal proteomics, particularly the expression of hippocampal iron metabolism-related proteins, could further influence cognitive impairment in ovariectomized mice.


Assuntos
Modelos Animais de Doenças , Compostos Férricos , Hipocampo , Ferro , Camundongos Endogâmicos C57BL , Ovariectomia , Animais , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Camundongos , Ferro/metabolismo , Compostos Férricos/toxicidade , Compostos Férricos/farmacologia , Aprendizagem em Labirinto/efeitos dos fármacos , Disfunção Cognitiva/metabolismo , Transtornos Cognitivos/patologia , Transtornos Cognitivos/induzido quimicamente , Superóxido Dismutase/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Receptores da Transferrina/metabolismo
9.
Ecotoxicol Environ Saf ; 283: 116942, 2024 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-39216217

RESUMO

Metal tolerance protein (MTP) is a cation transporter that plays an important role in tolerance to heavy metal stress. However, thus far, there has been no genome-wide investigation of the MTP gene family in Quercus plants. Quercus dentata is one of the main constructive species of forest in northern China. It has strong tolerance to a variety of heavy metal stresses. In this study, 25 MTPs were identified from the Q. dentata genome and classified into three subfamilies and seven groups according to their sequence characteristics and phylogenetic relationships. Both tandem and segmental duplication events contributed to the expansion of the QdMTP gene family. Interestingly, all 10 tandem duplication events contributed to the expansion of the Mn-CDF subfamily. The expression of Mn-CDF subfamily members in different organs and tissues of Q. dentata was different, and they responded differently to manganese, iron, zinc and cadmium stress treatments. QdMTP10.7, a member of the Mn-CDF subfamily, enhanced yeast growth under manganese, zinc and iron stresses. The subcellular localization in tobacco leaf epidermis cells showed that QdMTP10.7 was located in vacuoles. These data generated from this study provide an important foundation to elucidate the biological roles of QdMTP genes related to heavy metal tolerance in Q. dentata.


Assuntos
Metais Pesados , Filogenia , Proteínas de Plantas , Quercus , Metais Pesados/toxicidade , Quercus/genética , Quercus/efeitos dos fármacos , Proteínas de Plantas/genética , Estresse Fisiológico/genética , Estresse Fisiológico/efeitos dos fármacos , China , Proteínas de Transporte de Cátions/genética , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Genoma de Planta , Poluentes do Solo/toxicidade
10.
Proc Natl Acad Sci U S A ; 121(35): e2402491121, 2024 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-39163336

RESUMO

Activating Ca2+-sensitive enzymes of oxidative metabolism while preventing calcium overload that leads to mitochondrial and cellular injury requires dynamic control of mitochondrial Ca2+ uptake. This is ensured by the mitochondrial calcium uptake (MICU)1/2 proteins that gate the pore of the mitochondrial calcium uniporter (mtCU). MICU1 is relatively sparse in the heart, and recent studies claimed the mammalian heart lacks MICU1 gating of mtCU. However, genetic models have not been tested. We find that MICU1 is present in a complex with MCU in nonfailing human hearts. Furthermore, using murine genetic models and pharmacology, we show that MICU1 and MICU2 control cardiac mitochondrial Ca2+ influx, and that MICU1 deletion alters cardiomyocyte mitochondrial calcium signaling and energy metabolism. MICU1 loss causes substantial compensatory changes in the mtCU composition and abundance, increased turnover of essential MCU regulator (EMRE) early on and, later, of MCU, that limit mitochondrial Ca2+ uptake and allow cell survival. Thus, both the primary consequences of MICU1 loss and the ensuing robust compensation highlight MICU1's relevance in the beating heart.


Assuntos
Sinalização do Cálcio , Proteínas de Ligação ao Cálcio , Cálcio , Proteínas de Transporte de Cátions , Proteínas de Transporte da Membrana Mitocondrial , Miócitos Cardíacos , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Ligação ao Cálcio/genética , Camundongos , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/genética , Humanos , Proteínas de Transporte de Cátions/metabolismo , Proteínas de Transporte de Cátions/genética , Miócitos Cardíacos/metabolismo , Sinalização do Cálcio/fisiologia , Cálcio/metabolismo , Mitocôndrias Cardíacas/metabolismo , Canais de Cálcio/metabolismo , Canais de Cálcio/genética , Camundongos Knockout , Miocárdio/metabolismo , Masculino
11.
Int J Mol Sci ; 25(16)2024 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-39201626

RESUMO

Iron is an essential element for human health. In humans, dysregulated iron homeostasis can result in a variety of disorders and the development of cancers. Enhanced uptake, redistribution, and retention of iron in cancer cells have been suggested as an "iron addiction" pattern in cancer cells. This increased iron in cancer cells positively correlates with rapid tumor growth and the epithelial-to-mesenchymal transition, which forms the basis for tumor metastasis. However, the source of iron and the mechanisms cancer cells adopt to actively acquire iron is not well understood. In the present study, we report, for the first time, that the peptide hormone, prolactin, exhibits a novel function in regulating iron distribution, on top of its well-known pro-lactating role. When stimulated by prolactin, breast cancer cells increase CD44, a surface receptor mediating the endocytosis of hyaluronate-bound iron, resulting in the accumulation of iron in cancer cells. In contrast, macrophages, when treated by prolactin, express more ferroportin, the only iron exporter in cells, giving rise to net iron output. Interestingly, when co-culturing macrophages with pre-stained labile iron pools and cancer cells without any iron staining, in an iron free condition, we demonstrate direct iron flow from macrophages to cancer cells. As macrophages are one of the major iron-storage cells and it is known that macrophages infiltrate tumors and facilitate their progression, our work therefore presents a novel regulatory role of prolactin to drive iron flow, which provides new information on fine-tuning immune responses in tumor microenvironment and could potentially benefit the development of novel therapeutics.


Assuntos
Neoplasias da Mama , Receptores de Hialuronatos , Ferro , Macrófagos , Prolactina , Prolactina/metabolismo , Ferro/metabolismo , Receptores de Hialuronatos/metabolismo , Macrófagos/metabolismo , Humanos , Feminino , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Animais , Camundongos , Proteínas de Transporte de Cátions
12.
Cell Mol Life Sci ; 81(1): 357, 2024 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-39158587

RESUMO

SLC30A9 (ZnT9) is a mitochondria-resident zinc transporter. Mutations in SLC30A9 have been reported in human patients with a novel cerebro-renal syndrome. Here, we show that ZnT9 is an evolutionarily highly conserved protein, with many regions extremely preserved among evolutionarily distant organisms. In Drosophila melanogaster (the fly), ZnT9 (ZnT49B) knockdown results in acutely impaired movement and drastic mitochondrial deformation. Severe Drosophila ZnT9 (dZnT9) reduction and ZnT9-null mutant flies are pupal lethal. The phenotype of dZnT9 knockdown can be partially rescued by mouse ZnT9 expression or zinc chelator TPEN, indicating the defect of dZnT9 loss is indeed a result of zinc dyshomeostasis. Interestingly, in the mouse, germline loss of Znt9 produces even more extreme phenotypes: the mutant embryos exhibit midgestational lethality with severe development abnormalities. Targeted mutagenesis of Znt9 in the mouse brain leads to serious dwarfism and physical incapacitation, followed by death shortly. Strikingly, the GH/IGF-1 signals are almost non-existent in these tissue-specific knockout mice, consistent with the medical finding in some human patients with severe mitochondrial deficiecny. ZnT9 mutations cause mitochondrial zinc dyshomeostasis, and we demonstrate mechanistically that mitochondrial zinc elevation quickly and potently inhibits the activities of respiration complexes. These results reveal the critical role of ZnT9 and mitochondrial zinc homeostasis in mammalian development. Based on our functional analyses, we finally discussed the possible nature of the so far identified human SLC30A9 mutations.


Assuntos
Proteínas de Transporte de Cátions , Desenvolvimento Embrionário , Mitocôndrias , Zinco , Animais , Proteínas de Transporte de Cátions/metabolismo , Proteínas de Transporte de Cátions/genética , Humanos , Zinco/metabolismo , Camundongos , Mitocôndrias/metabolismo , Desenvolvimento Embrionário/genética , Drosophila melanogaster/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/embriologia , Evolução Molecular , Camundongos Knockout , Sequência de Aminoácidos , Proteínas Mitocondriais/metabolismo , Proteínas Mitocondriais/genética , Fatores de Transcrição , Proteínas de Ciclo Celular
13.
Sheng Li Xue Bao ; 76(4): 507-516, 2024 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-39192784

RESUMO

The present study aimed to investigate the occurrence of ferroptosis in mouse hippocampal tissue and changes in related pathways after exposure to high-altitude hypoxia. A low-pressure hypoxia model was established using a high-altitude environment at 4 010 m. HE staining was used to observe morphological changes in mouse hippocampal tissue, immunohistochemical staining was used to observe lipid peroxidation levels in hippocampal tissue, and corresponding kits were used to measure malondialdehyde (MDA), reduced glutathione (GSH), and Fe2+ levels in hippocampal tissue. Western blot was used to detect glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), ferritin heavy chain 1 (FTH1), ferroportin 1 (FPN1), transferrin receptor 1 (TfR1), ferroptosis suppressor protein 1 (FSP1), and acyl-CoA synthase long chain family member 4 (ACSL4). The results showed that, compared with the plain control group, the mice exposed to high-altitude hypoxia for 1, 3, 7, and 14 d exhibited significant pathological damage, disordered arrangement, and obvious nuclear condensation in the dentate gyrus of the hippocampus. Compared with the plain control group, high-altitude hypoxia exposure increased 4-hydroxynonenal (4-HNE) content in the dentate gyrus and hippocampal MDA content, whereas significantly decreased hippocampal GSH content. Compared with the plain control group, the Fe2+ content in the hippocampus of mice exposed to high-altitude hypoxia for 14 d significantly increased. Compared with the plain control group, the protein expression levels of GPX4, FTH1, FPN1, TfR1, and FSP1 in the hippocampus of mice exposed to high-altitude hypoxia were significantly down-regulated (SLC7A11 was significantly down-regulated only in the 7-d high-altitude hypoxia exposure group), while the protein expression level of ACSL4 was only significantly up-regulated in the 14-d high-altitude hypoxia exposure group. These results suggest that exposure to high-altitude hypoxia for 14 d can reduce GSH synthesis in mouse hippocampus, down-regulate GPX4 expression, lead to GSH metabolism disorders, inhibit iron storage and efflux, promote lipid peroxidation reaction, and inhibit CoQ10H2's anti-lipid peroxidation effect, ultimately leading to ferroptosis.


Assuntos
Doença da Altitude , Ferroptose , Hipocampo , Hipóxia , Animais , Ferroptose/fisiologia , Hipocampo/metabolismo , Camundongos , Hipóxia/metabolismo , Hipóxia/fisiopatologia , Masculino , Doença da Altitude/metabolismo , Doença da Altitude/fisiopatologia , Peroxidação de Lipídeos , Receptores da Transferrina/metabolismo , Altitude , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Glutationa/metabolismo , Malondialdeído/metabolismo , Ferro/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Sistema y+ de Transporte de Aminoácidos/metabolismo , Sistema y+ de Transporte de Aminoácidos/genética
14.
Int J Mol Sci ; 25(15)2024 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-39125916

RESUMO

Understanding the role of iron in ethanol-derived hepatic stress could help elucidate the efficacy of dietary or clinical interventions designed to minimize liver damage from chronic alcohol consumption. We hypothesized that normal levels of iron are involved in ethanol-derived liver damage and reduced dietary iron intake would lower the damage caused by ethanol. We used a pair-fed mouse model utilizing basal Lieber-DeCarli liquid diets for 22 weeks to test this hypothesis. In our mouse model, chronic ethanol exposure led to mild hepatic stress possibly characteristic of early-stage alcoholic liver disease, seen as increases in liver-to-body weight ratios. Dietary iron restriction caused a slight decrease in non-heme iron and ferritin (FeRL) expression while it increased transferrin receptor 1 (TfR1) expression without changing ferroportin 1 (FPN1) expression. It also elevated protein lysine acetylation to a more significant level than in ethanol-fed mice under normal dietary iron conditions. Interestingly, iron restriction led to an additional reduction in nicotinamide adenine dinucleotide (NAD+) and NADH levels. Consistent with this observation, the major mitochondrial NAD+-dependent deacetylase, NAD-dependent deacetylase sirtuin-3 (SIRT3), expression was significantly reduced causing increased protein lysine acetylation in ethanol-fed mice at normal and low-iron conditions. In addition, the detection of superoxide dismutase 1 and 2 levels (SOD1 and SOD2) and oxidative phosphorylation (OXPHOS) complex activities allowed us to evaluate the changes in antioxidant and energy metabolism regulated by ethanol consumption at normal and low-iron conditions. We observed that the ethanol-fed mice had mild liver damage associated with reduced energy and antioxidant metabolism. On the other hand, iron restriction may exacerbate certain activities of ethanol further, such as increased protein lysine acetylation and reduced antioxidant metabolism. This metabolic change may prove a barrier to the effectiveness of dietary reduction of iron intake as a preventative measure in chronic alcohol consumption.


Assuntos
Antioxidantes , Metabolismo Energético , Etanol , Animais , Camundongos , Acetilação/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Antioxidantes/metabolismo , Masculino , Ferro/metabolismo , Superóxido Dismutase-1/metabolismo , Superóxido Dismutase-1/genética , Superóxido Dismutase/metabolismo , Lisina/metabolismo , Fígado/metabolismo , Fígado/efeitos dos fármacos , Receptores da Transferrina/metabolismo , Sirtuína 3/metabolismo , Sirtuína 3/genética , NAD/metabolismo , Ferritinas/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Proteínas de Transporte de Cátions/genética , Estresse Oxidativo/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/patologia , Hepatopatias Alcoólicas/etiologia
16.
Int J Mol Sci ; 25(15)2024 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-39125839

RESUMO

Arbuscular mycorrhizal (AM) fungi are well known for enhancing phosphorus uptake in plants; however, their regulating roles in cation transporting gene family, such as natural resistance-associated macrophage protein (NRAMP), are still limited. Here, we performed bioinformatics analysis and quantitative expression assays of tomato SlNRAMP 1 to 5 genes under nutrient deficiency and cadmium (Cd) stress in response to AM symbiosis. These five SlNRAMP members are mainly located in the plasma or vacuolar membrane and can be divided into two subfamilies. Cis-element analysis revealed several motifs involved in phytohormonal and abiotic regulation in their promoters. SlNRAMP2 was downregulated by iron deficiency, while SlNRAMP1, SlNRAMP3, SlNRAMP4, and SlNRAMP5 responded positively to copper-, zinc-, and manganese-deficient conditions. AM colonization reduced Cd accumulation and expression of SlNRAMP3 but enhanced SlNRAMP1, SlNRAMP2, and SlNRMAP4 in plants under Cd stress. These findings provide valuable genetic information for improving tomato resilience to nutrient deficiency and heavy metal stress by developing AM symbiosis.


Assuntos
Cádmio , Regulação da Expressão Gênica de Plantas , Micorrizas , Proteínas de Plantas , Solanum lycopersicum , Estresse Fisiológico , Simbiose , Micorrizas/fisiologia , Solanum lycopersicum/microbiologia , Solanum lycopersicum/genética , Solanum lycopersicum/metabolismo , Cádmio/toxicidade , Cádmio/metabolismo , Simbiose/genética , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Estresse Fisiológico/genética , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo
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