Journal of Biological Chemistry最新文献

{"title":"Cysteine Import via the High Affinity Glutathione Transporter Hgt1 Rescues Glutathione Auxotrophy in Yeast.","authors":"Crystal C McGee, Tirthankar Bandyopadhyay, Cailin N McCracken, Evan Talib, Courtney E Patterson, Caryn E Outten","doi":"10.1016/j.jbc.2024.108131","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.108131","url":null,"abstract":"<p><p>Glutathione (GSH) is an abundant thiol-containing tripeptide that functions in redox homeostasis, protein folding, and iron metabolism. In Saccharomyces cerevisiae, GSH depletion leads to increased sensitivity to oxidants and other toxic compounds, disruption of Fe-S cluster biogenesis, and eventually cell death. GSH pools are supplied by intracellular biosynthesis and GSH import from the extracellular environment. Consequently, in GSH-depleted growth media, deletion of the gene encoding the first enzyme in the GSH biosynthetic pathway (GSH1), is lethal in yeast. At the other extreme, GSH overaccumulation via overexpression of the high affinity GSH transporter Hgt1 is also toxic to cells, leading to reductive stress. Here we engineered a yeast strain that combines GSH1 deletion with HGT1 overexpression to study the cellular effects of oscillating between GSH deplete and replete conditions. Surprisingly, we find that constitutive expression of HGT1 in gsh1Δ cells rescues the GSH auxotrophy of this strain. We also show that addition of cysteine or cysteine derivatives to the growth media is required for this rescue. GSH limitation in yeast causes intracellular iron overload due to disruption of an iron-sulfur (Fe-S) cluster dependent pathway that regulates the activity of the low iron sensing transcription factors Aft1 and Aft2. Analysis of iron regulation and other Fe-S cluster dependent pathways reveals that HGT1 overexpression partially alleviates the iron starvation-like response of gsh1Δ cells. Taken together, these results suggest that HGT1 overexpression facilitates import of cysteine or cysteine derivatives that allow limited Fe-S cluster biogenesis to sustain cell growth in the absence of GSH.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"108131"},"PeriodicalIF":4.0,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ID3 promotes erythroid differentiation and is repressed by a TAL1/PRMT6 complex.","authors":"Vivien Heller, Lei Wang, Edith Schneider, Mirjam Gerstner, Luana Bajer, Robin Decker, Halvard Boenig, Joern Lausen","doi":"10.1016/j.jbc.2024.108119","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.108119","url":null,"abstract":"<p><p>Erythropoiesis is controlled by transcription factors that recruit epigenetic cofactors to establish and maintain erythrocyte-specific gene expression patterns while repressing alternative lineage commitment. The transcription factor TAL1 is critical for establishing erythroid gene expression. It acts as an activator or repressor of genes, depending on associated epigenetic cofactors. Understanding the epigenetic function of TAL1 during erythropoiesis is key to improving in vitro erythroid differentiation and understanding pathological erythropoiesis. Therefore, the regulatory mechanisms that control the function of TAL1 during erythropoiesis are under intense investigation. Here we show that TAL1 interacts with PRMT6 on the ID3 gene in K562 and hCD34+ cells. The ID protein family is a critical transcriptional regulator of hematopoietic cell differentiation. We show that TAL1 and PRMT6 are present at the ID3 promoter, and that TAL1 is involved in the recruitment of PRMT6. Here, PRMT6 epigenetically regulates ID3 expression by mediating H3R2me2a. Thus, TAL1/PRMT6 epigenetically represses ID3 expression in progenitors, which is relieved upon erythroid differentiation, leading to increased ID3 expression. Overexpression of ID3 in primary hCD34+ cells enhances erythropoiesis. Our results show that a TAL1/PRMT6 complex regulates genes important for erythropoiesis, such as ID3. Manipulation of ID3 expression may be a way to promote in vitro differentiation of hCD34+ cells into erythrocytes.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"108119"},"PeriodicalIF":4.0,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deafness-associated mitochondrial 12S rRNA mutation reshapes mitochondrial and cellular homeostasis.","authors":"Yunfan He, Zhining Tang, Gao Zhu, Luhang Cai, Chao Chen, Min-Xin Guan","doi":"10.1016/j.jbc.2024.108124","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.108124","url":null,"abstract":"<p><p>Human mitochondrial 12S ribosomal RNA (rRNA) 1555A>G mutation has been associated with aminoglycoside-induced and nonsyndromic deafness in many families worldwide. Our previous investigation revealed that the m.1555A>G mutation impaired mitochondrial translation and oxidative phosphorylation (OXPHOS). However, the mechanisms by which mitochondrial dysfunctions induced by m.1555A>G mutation regulate intracellular signaling for mitochondrial and cellular integrity remain poorly understood. Here, we demonstrated that the m.1555A>G mutation downregulated the expression of nuclear-encoded subunits of complexes I and IV but upregulated the expression of assemble factors for OXPHOS complexes, using cybrids derived from one hearing-impaired Chinese subject bearing the m.1555A>G mutation and from one hearing normal control lacking the mutation. These alterations resulted in the aberrant assembly, instability and reduced activities of respiratory chain enzyme complexes I, IV and V, rate of oxygen consumption, and diminished ATP production. Furthermore, the mutant cell lines carrying the m.1555A>G mutation exhibited decreased membrane potential and increased the production of reactive oxygen species. The aberrant assembly and biogenesis of OXPHOS impacted mitochondrial quality controls, including the imbalance of mitochondrial dynamics via increasing fission with abnormal mitochondrial morphology and impaired mitophagy. Strikingly, the cells bearing the m.1555A>G mutation revealed the upregulation of both ubiquitin-dependent and independent mitophagy pathways, evidenced by increasing the levels of Parkin, Pink, BNIP3L and NIX. The m.1555A>G mutation-induced deficiencies ameliorate the cell homeostasis via elevating the autophagy process and upregulating apoptotic pathways. Our findings provide new insights into pathophysiology of mitochondrial deafness arising from reshaping mitochondrial and cellular homeostasis due to 12S rRNA 1555A>G mutation.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"108124"},"PeriodicalIF":4.0,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881803","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Calmodulin enhances mTORC1 signaling by preventing TSC2-Rheb binding.","authors":"Yuna Amemiya, Yuichiro Ioi, Makoto Araki, Kenji Kontani, Masatoshi Maki, Hideki Shibata, Terunao Takahara","doi":"10.1016/j.jbc.2024.108122","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.108122","url":null,"abstract":"<p><p>The mechanistic target of rapamycin complex 1 (mTORC1) functions as a master regulator of cell growth and proliferation. We previously demonstrated that intracellular calcium ion (Ca²⁺) concentration modulates the mTORC1 pathway via binding of the Ca²⁺ sensor protein calmodulin (CaM) to tuberous sclerosis complex 2 (TSC2), a critical negative regulator of mTORC1. However, the precise molecular mechanism by which Ca²⁺/CaM modulates mTORC1 activity remains unclear. Here, we performed a binding assay based on nano-luciferase reconstitution, a method for detecting weak interactions between TSC2 and its target, Ras homolog enriched in brain (Rheb), an activator of mTORC1. CaM inhibited the binding of TSC2 to Rheb in a Ca²⁺-dependent manner. Live-cell imaging analysis indicated increased interaction between the CaM-binding region of TSC2 and CaM in response to elevated intracellular Ca²⁺ levels. Furthermore, treatment with carbachol, an acetylcholine analog, elevated intracellular Ca²⁺ levels, and activated mTORC1. Notably, carbachol-induced activation of mTORC1 was inhibited by CaM inhibitors, corroborating the role of Ca²⁺/CaM in promoting the mTORC1 pathway. Consistent with the effect of Ca²⁺/CaM on the TSC2-Rheb interaction, increased intracellular Ca²⁺ concentration promoted the dissociation of TSC2 from lysosomes without affecting Akt-dependent phosphorylation of TSC2, suggesting that the regulatory mechanism of TSC2 by Ca²⁺/CaM is distinct from the previously established action mechanism of TSC2. Collectively, our findings offer mechanistic insights into TSC2-Rheb regulation mediated by Ca²⁺/CaM, which links Ca²⁺ signaling to mTORC1 activation.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"108122"},"PeriodicalIF":4.0,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analysis of eIF4E-family members in Fungi contributes to their classification in eukaryotes.","authors":"Greco Hernández, Daniela Ross-Kaschitza, Gabriel Moreno-Hagelsieb, Alejandra García, Dora Emma Vélez, Blanca Licia Torres","doi":"10.1016/j.jbc.2024.108129","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.108129","url":null,"abstract":"<p><p>The kingdom of fungi contains highly diverse species. However, fundamental processes sustaining life such as RNA metabolism are much less comparatively studied in Fungi than in other kingdoms. A key factor in the regulation of mRNA expression is the cap-binding protein eIF4E, which plays roles in mRNA nuclear export, storage and translation. The advent of massive genomics has unveiled a constellation of eIF4E-family members across eukaryotes. However, how this protein diverged in fungal species remains largely unexplored. Here, we studied the genome of 538 species from six evolutionarily distant phyla and retrieved 1462 eIF4E cognates. The analyzed species contained 1-7 paralogs. We sorted the different cognates in six phylogenetically coherent clades, that we termed Class I-VII (mammalian Class III was absent in Fungi). Proteins from Classes IV-VII did not match the current eIF4Es classification, that is based on variations in the residues equivalent to W43 and W56 of the human protein. eIF4Es from other eukaryotes do not fit into this classification either. Thus, we have updated the eIF4E categorization based on cladistics and the presence of cap-binding amino acids to better fit eIF4E´s diversity across eukaryotes. Finally, we predicted the structure of the global protein and the cap-binding pocket, and experimentally tested the ability to rescue the lack of endogenous eIF4E in Saccharomyces cerevisiae of representative members of each of the six classes of fungal eIF4E.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"108129"},"PeriodicalIF":4.0,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Conformational transitions of Streptococcus pyogenes Cas9 induced by salt and single-guide RNA binding.","authors":"Yufan He, Nikita Zalenski, Anthony A Stephenson, Austin T Raper, Chiran Ghimire, Zucai Suo","doi":"10.1016/j.jbc.2024.108120","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.108120","url":null,"abstract":"<p><p>Streptococcus pyogenes (Sp) Cas9 has been widely utilized to edit genomes across diverse species. To achieve high efficiency and specificity as a gene editing enzyme, Sp Cas9 undergoes a series of sequential conformational changes during substrate binding and catalysis. Here, we employed single molecule FRET techniques to investigate the effect of different KCl concentrations on conformational dynamics of Sp Cas9 in the presence or absence of a single-guide RNA (sgRNA). In the absence of sgRNA and at low KCl concentrations (75 mM), apo Cas9 surprisingly exhibited two distinct conformations: a primary auto-inhibited open conformation (Cas9^apo) and a secondary sgRNA-bound-like conformation (Cas9^X). Interestingly, increase in buffer KCl concentration led to a linear increase in the Cas9^X population and a corresponding decrease in the Cas9^apo population. In contrast, changes in KCl concentration exerted the opposite effects on the Cas9^X and Cas9^apo populations in the presence of sgRNA. Collectively, our findings by using KCl concentration as the probe, suggest Cas9 might employ a conformational sampling mechanism, in addition to the more common induced-fit mechanism established by us previously, for sgRNA binding.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"108120"},"PeriodicalIF":4.0,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A new regulation mechanism for KCNN4, the Ca²⁺-dependent K⁺ channel, by molecular interactions with the Ca²⁺pump PMCA4b.","authors":"Benoit Allegrini, Morgane Mignotet, Raphaël Rapetti-Mauss, Franck Borgese, Olivier Soriani, Hélène Guizouarn","doi":"10.1016/j.jbc.2024.108114","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.108114","url":null,"abstract":"<p><p>KCNN4, a Ca²⁺-activated K⁺ channel, is involved in various physiological and pathological processes. It is essential for epithelial transport, immune system and other physiological mechanisms but its activation is also involved in cancer pathophysiology as well as red blood cell disorders (RBC). The activation of KCNN4 in RBC leads to loss of KCl and water, a mechanism known as the \"Gardos effect\" described seventy years ago. This Ca²⁺ induced dehydration is irreversible in human RBC and must be tightly controlled to prevent not only hemolysis but also alterations in RBC rheological properties. In this study, we have investigated the regulation of KCNN4 activity after changes in RBC Ca²⁺ concentration. Using electrophysiology, immunoprecipitation and proximity ligation assay in HEK293 transfected cells, K562 cells or RBC, we have found that KCNN4 and the Ca²⁺ pump PMCA4b interact tightly with each other, such that the C-terminal domain of PMCA4b regulates KCNN4 activity, independently of the Ca²⁺ extrusion activity of the pump. This regulation was not restricted to KCNN4: the small-conductance Ca²⁺-activated K⁺ channel KCNN2 was similarly regulated by the calcium pump. We propose a new mechanism that could control KCNN4 activity by a molecular inhibitory interaction with PMCA4b. It is suggested that this mechanism could attenuate erythrocyte dehydration in response to an increase in intracellular Ca²⁺.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"108114"},"PeriodicalIF":4.0,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dilated cardiomyopathy variant R14del increases phospholamban pentamer stability, blunting dynamic regulation of calcium.","authors":"Sean R Cleary, Allen C T Teng, Audrey Deyawe Kongmeneck, Xuan Fang, Taylor A Phillips, Ellen E Cho, Rhys A Smith, Patryk Karkut, Catherine A Makarewich, Peter M Kekenes-Huskey, Anthony O Gramolini, Seth L Robia","doi":"10.1016/j.jbc.2024.108118","DOIUrl":"10.1016/j.jbc.2024.108118","url":null,"abstract":"<p><p>The sarco(endo)plasmic reticulum Ca²⁺ ATPase (SERCA) is a membrane transporter that creates and maintains intracellular Ca²⁺ stores. In the heart, SERCA is regulated by an inhibitory interaction with the monomeric form of the transmembrane micropeptide phospholamban (PLB). PLB also forms avid homo-pentamers, and dynamic exchange of PLB between pentamers and SERCA is an important determinant of cardiac responsiveness to exercise. Here, we investigated two naturally occurring pathogenic variants of PLB: a cysteine substitution of Arg9 (R9C) and an in-frame deletion of Arg14 (R14del). Both variants are associated with dilated cardiomyopathy. We previously showed that the R9C mutation causes disulfide crosslinking and hyperstabilization of pentamers. While the pathogenic mechanism of R14del is unclear, we hypothesized this mutation may also alter pentamer stability. Immunoblots revealed a significantly increased pentamer:monomer ratio for R14del-PLB compared to WT-PLB. We quantified homo-oligomerization and SERCA-binding in live cells using fluorescence resonance energy transfer (FRET) microscopy. R14del-PLB showed increased affinity for homo-oligomerization and decreased binding affinity for SERCA compared to WT. The data suggest that, like R9C, the R14del mutation stabilizes PLB in pentamers, decreasing its ability to regulate SERCA. The R14del mutation reduces the rate of PLB unbinding from pentamers after transient elevations of Ca²⁺, limiting the recovery of PLB-SERCA complexes. A computational model predicted that hyperstabilization of PLB pentamers by R14del impairs the ability of cardiac Ca²⁺ handling to respond to changing heart rates between rest and exercise. We postulate that impaired responsiveness to physiological stress contributes to arrhythmogenesis in human carriers of the R14del mutation.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"108118"},"PeriodicalIF":4.0,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142877048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MAP3K4 signaling regulates HDAC6 and TRAF4 coexpression and stabilization in trophoblast stem cells^†.","authors":"Hannah A Nelson, Nathan A Mullins, Amy N Abell","doi":"10.1016/j.jbc.2024.108116","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.108116","url":null,"abstract":"<p><p>Mitogen-activated protein kinase kinase kinase 4 (MAP3K4) promotes fetal and placental growth and development, with MAP3K4 kinase inactivation resulting in placental insufficiency and fetal growth restriction. MAP3K4 promotes key signaling pathways including JNK, p38, and PI3K/Akt, leading to activation of CREB-binding protein. MAP3K4 kinase inactivation results in loss of these pathways and gain of histone deacetylase 6 (HDAC6) expression and activity. Tumor necrosis factor receptor-associated factor 4 (TRAF4) binds MAP3K4 and promotes MAP3K4 activation of downstream pathways in the embryo; however, the role of TRAF4 and its association with MAP3K4 in the placenta is unknown. Our analyses of murine placenta single-cell RNA-Seq data showed that Traf4 is coexpressed with Map3k4 in trophoblast stem (TS) cells and labyrinth progenitors, whereas Hdac6 expression is higher in differentiated trophoblasts. We demonstrate that, like HDAC6, TRAF4 expression is increased in MAP3K4 kinase-inactive TS (TS^KI) cells and upon inhibition of MAP3K4-dependent pathways in WT TS cells. Moreover, Hdac6 shRNA knockdown in TS^KI cells reduces TRAF4 protein expression. We found that HDAC6 forms a protein complex with TRAF4 in TS cells and promotes TRAF4 expression in the absence of HDAC6 deacetylase activity. Finally, we examine the relationships among MAP3K4, TRAF4, and HDAC6 in the developing placenta, finding a previously unknown switch in coexpression of Traf4 with Map3k4 versus Traf4 with Hdac6 during differentiation of the placental labyrinth. Together, our findings identify previously unknown mechanisms of MAP3K4 and HDAC6 coregulation of TRAF4 in TS cells and highlight these MAP3K4, TRAF4, and HDAC6 associations during placental development.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"108116"},"PeriodicalIF":4.0,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142877055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acute heat stress upregulates Akr1b3 through Nrf-2 to increase endogenous fructose leading to kidney injury.","authors":"Shuai Wang, Xuan Pang, Yujuan Cai, Xue Tian, Jingyi Bai, Mingchuan Xi, Jiaxue Cao, Long Jin, Xun Wang, Tao Wang, Diyan Li, Mingzhou Li, Xiaolan Fan","doi":"10.1016/j.jbc.2024.108121","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.108121","url":null,"abstract":"<p><p>In recent years, the prevalence of extremely high-temperature climates, has led to an increase in cases of acute heat stress, which has been identified as a contributing factor to various kidney diseases. Fructose, the end product of the polyol pathway, has been linked to kidney conditions such as kidney stones, chronic kidney disease and acute kidney injury. However, the relationship between acute heat stress and kidney injury caused by endogenous fructose remains unclear. The study found that acute heat stress triggers the production of reactive oxygen species (ROS), which in turn activate the Nrf-2 and Akr1b3 leading to an increase in endogenous fructose levels in kidney cells. It was further demonstrated that the elevated levels of endogenous fructose play a crucial role in causing damage to kidney cells. Moreover, inhibiting Nrf-2 effectively mitigated kidney damage induced by acute heat stress by reducing endogenous fructose levels. These findings underscore the detrimental impact of excessive fructose resulting from acute stress on kidney function, offering a novel perspective for future research on the prevention and treatment of acute heat stress-induced kidney injury.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"108121"},"PeriodicalIF":4.0,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142877041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}