International Journal of Biological Sciences最新文献

{"title":"Accelerating Ligand Discovery for Insect Odorant Receptors.","authors":"Arthur Comte, Maxence Lalis, Ludvine Brajon, Riccardo Moracci, Nicolas Montagné, Jérémie Topin, Emmanuelle Jacquin-Joly, Sébastien Fiorucci","doi":"10.7150/ijbs.105648","DOIUrl":"10.7150/ijbs.105648","url":null,"abstract":"<p><p>Odorant receptors (ORs) are main actors of the insects peripheral olfactory system, making them prime targets for pest control through olfactory disruption. Traditional methods employed in the context of chemical ecology for identifying OR ligands rely on analyzing compounds present in the insect's environment or screening molecules with structures similar to known ligands. However, these approaches can be time-consuming and constrained by the limited chemical space they explore. Recent advances in OR structural understanding, coupled with scientific breakthroughs in protein structure prediction, have facilitated the application of Structure-Based Virtual Screening (SBVS) techniques for accelerated ligand discovery. Here, we report the first successful application of SBVS to insect ORs. We developed a unique workflow that combines molecular docking predictions, <i>in vivo</i> validation and behavioral assays to identify new behaviorally active volatiles for non-pheromonal receptors. This work serves as a proof of concept, laying the groundwork for future studies and highlighting the need for improved computational approaches. Finally, we propose a simple model for predicting receptor response spectra based on the hypothesis that the binding pocket properties partially encode this information, as suggested by our results on <i>Spodoptera littoralis</i> ORs.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 5","pages":"2101-2117"},"PeriodicalIF":8.2,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11900807/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thrombospondin 1 Promotes Cytoskeleton Remodeling, Dedifferentiation, and Pulmonary Metastasis through ITGA1 and ITGA6 in Osteosarcoma.","authors":"Enjie Xu, Zhen Huang, Kunpeng Zhu, Jianping Hu, Xiaolong Ma, Yongjie Wang, Jiazhuang Zhu, Chunlin Zhang","doi":"10.7150/ijbs.93678","DOIUrl":"10.7150/ijbs.93678","url":null,"abstract":"<p><p>Dedifferentiation of osteosarcoma cells leads to poor prognosis. We plan to identify the key molecules that are involved in cell dedifferentiation and explore how they promote the pulmonary metastasis of osteosarcoma cells. We performed a sphere formation assay and confirmed that the spheroid cells could be redifferentiated into osteoblasts, adipocytes, and chondrocytes in specific medium, and the stem cell-like markers Stro-1 and CD117 were detected on the cell surface, which indicated that the spheroid cells were dedifferentiated cells. Thrombospondin 1 (THBS1) and ITGAs were identified as the key molecules in dedifferentiation through mRNA-seq and analysis, and osteosarcoma patients with higher THBS1 expression had a worse prognosis than those with lower THBS1 expression. THBS1 promotes the accumulation of ITGA1 and ITGA6 on the cell membrane in the early phase of dedifferentiation, thereby increasing the phosphorylation of FAK, RasGRF1, and MLC2 in the cytoplasm and promoting cytoskeleton remodeling. Our results suggest that THBS1 promotes cell dedifferentiation and pulmonary metastasis by promoting cytoskeletal remodeling and that ITGA1 and ITGA6 play important roles in mediating extracellular to intracellular signals; this mediating effect takes place mainly in the early phase of dedifferentiation.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 5","pages":"2083-2100"},"PeriodicalIF":8.2,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11900803/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Core transcriptional regulatory circuitry molecule ZNF217 promotes AML cell proliferation by up-regulating MYB.","authors":"Bi Zhou, Fang Fang, YongPing Zhang, ZhiHeng Li, YiXin Hu, Yan Li, WanYan Jiao, YuMeng Wu, XiaoMei Wan, Ying Yang, FenLi Zhang, Ling Xu, TongTing Ji, Jian Pan, ShaoYan Hu","doi":"10.7150/ijbs.103211","DOIUrl":"10.7150/ijbs.103211","url":null,"abstract":"<p><p>Leukemia is characterized by multiple rearrangements of signal transduction genes and overexpression of nonmutated genes, such as transcription factors (TFs) genes. Super-enhancers (SEs) are prevalent in human cancers and are associated with the accumulation of numerous core TFs. SEs drive the expression of core TF genes by delivering robust transcriptional activation signals. Additionally, core TFs sustain the stability and activity of SEs through mutual auto-regulation loops, creating a positive feedback loop known as the Core Transcriptional Regulation Circuit (CRC). Using ChIP-seq data, we identified the involvement of the SE-related gene ZNF217 in acute myeloid leukemia (AML), in which its functional role and underlying mechanism remain unclear. We demonstrated that ZNF217, ELF1, MEF2D, RUNX2, and FOXP1 are likely integral components of the AML CRC through various experimental techniques, including CUT&Tag, short hairpin RNA (shRNA) transduction, and Luciferase reporter assays. Notably, ZNF217 was determined to be indispensable for the proliferation and viability of AML cells both <i>in vitro</i> and <i>in vivo</i>. Subsequent analysis of RNA-seq and CUT&Tag results identified MYB as a key direct target of ZNF217. Overall, our research highlights ZNF217 as a critical oncogene in AML and offers new insights into the transcriptional regulatory mechanisms at play in AML.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 5","pages":"1966-1983"},"PeriodicalIF":8.2,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11900805/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TMEM105 modulates disulfidptosis and tumor growth in pancreatic cancer via the β-catenin-c-MYC-GLUT1 axis.","authors":"Yifan Yin, Yixuan Sun, Hongfei Yao, Feng Yu, Qinyuan Jia, Chengyu Hu, Yuheng Zhu, Zonghao Duan, Dejun Liu, Yongwei Sun, Yanmiao Huo, Minwei Yang, Wei Liu","doi":"10.7150/ijbs.104598","DOIUrl":"10.7150/ijbs.104598","url":null,"abstract":"<p><p><b>Background:</b> Pancreatic cancer (PCa) is one of the most malignant diseases in the world. Different from ferroptosis and apoptosis, disulfidptosis is a novel type of cell death. The role of disulfidptosis in PCa remains uncovered. <b>Methods:</b> Disulfidptosis-related lncRNAs were identified based on TCGA-PAAD database. The disulfidptosis-related predict signature was constructed and verified by bioinformatic analysis. TCGA and GTEx database and Renji tissue microarray (TMA) were applied to determine <i>TMEM105</i> and its clinical significance. F-actin and PI staining were performed to detect disulfidptosis of PCa cells. The biological function of <i>TMEM105</i> was investigated by loss-of-function and gain-of-function assays. RNA pull-down and LC-MS/MS analysis were employed to detect <i>TMEM105</i> interacted proteins. The tissue samples from PCa patients with PET-CT information were utilized to validate the <i>TMEM105</i>-β-catenin-c-MYC-GLUT1 pathway in clinical settings. <b>Results:</b> A disulfidptosis-related predict signature, which was comprised of six lncRNAs, was constructed and validated by bioinformatic analysis. <i>TMEM105</i> was identified as disulfidptosis-related lncRNA whose high expression predicted a poor prognosis in PCa. Functional studies revealed that <i>TMEM105</i> promoted the growth and mitigated the disulfidptosis in PCa. Mechanically, <i>TMEM105</i> upregulated the expression of β-catenin by maintaining the protein stability through the proteosome pathway. The forced expressed β-catenin increased the expression of glycolysis-related transcription factor c-MYC, thus induced the transcription activity of GLUT1. <b>Conclusion:</b> These results revealed the growth acceleration and the disulfidptosis mitigation function of <i>TMEM105</i> in PCa. Targeting the <i>TMEM105</i>-β-catenin-c-MYC-GLUT1 pathway could be a potent therapy for PCa patients.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 5","pages":"1932-1948"},"PeriodicalIF":8.2,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11900826/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cyclin Y interacts with Chk1 to activate RRM2/STAT3 signaling and promotes radioresistance in non-small cell lung cancer.","authors":"Zhiwei Liu, Huichan Xue, Zhi Wang, Ye Zhao, Shuangbing Xu, Xiaorong Dong","doi":"10.7150/ijbs.106925","DOIUrl":"10.7150/ijbs.106925","url":null,"abstract":"<p><p>Radioresistance is one of the main reasons for the recurrence and metastasis of non-small cell lung cancer. Cyclin Y has been implicated in various cellular processes such as cell growth, proliferation, autophagy, and tumor progression. However, the function and regulatory mechanism of Cyclin Y in lung cancer radioresistance remain poorly understood. In this study, we find that Cyclin Y is overexpressed in non-small cell lung cancer and correlates with poor prognosis. Furthermore, knockdown of Cyclin Y results in inhibited cell growth and proliferation, increases DNA damage, impairs DNA damage repair, and enhances radiosensitivity <i>in vitro</i> and <i>in vivo</i>. Mechanistically, we uncover that Cyclin Y interacts with Chk1 and positively regulate both the mRNA and protein levels of RRM2, resulting in increased STAT3 phosphorylation. Rescue experiments confirm that the effects of Cyclin Y on lung cancer are mediated partially by RRM2. Collectively, we reveal for the first time that Cyclin Y promotes lung cancer radioresistance by binding to Chk1 to activate RRM2/STAT3 signaling, indicating that targeting Cyclin Y may be a promising strategy for enhancing the efficacy of radiotherapy in the treatment of non-small cell lung cancer.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 5","pages":"1999-2011"},"PeriodicalIF":8.2,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11900816/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Breaking Immunosuppression to Enhance Cancer Stem Cell-Targeted Immunotherapy.","authors":"Fang Zheng, Shan Zhang, Alfred E Chang, James J Moon, Max S Wicha, Shelley Xuelai Wang, Junhui Chen, Jixian Liu, Fanjun Cheng, Qiao Li","doi":"10.7150/ijbs.101025","DOIUrl":"10.7150/ijbs.101025","url":null,"abstract":"<p><p>Cancer stem cell (CSC)-targeted immunotherapy has emerged as a novel strategy in cancer treatment in the past decade. However, its efficacy is significantly limited due to the existence of host immune suppressive activity. Specifically, programmed cell death ligand-1 (PD-L1) is overexpressed in CSCs, and PD-L1 overexpressed CSCs create immunosuppressive milieu <i>via</i> interacting with various immune cells in tumor microenvironments (TME). Hence, novel immunotherapeutic strategies targeting CSCs with concurrent immunosuppression interruption will be promising in enhancing anti-CSC effects. These include dendritic cell (DC) and nanodisc (ND)-based vaccines to present CSC antigens in the forms of CSC lysate, CSC-marker proteins, and CSC-derived peptides to induce anti-CSC immunity. In addition, CSC-directed bispecific antibodies (BiAbs) and antibody drug conjugates (ADCs) have been developed to target CSCs effectively. Furthermore, chimeric antigen receptor (CAR)-T cell therapy and natural killer (NK) cell-based therapy targeting CSCs have achieved progress in both solid and hematologic tumors, and inhibition of CSC associated signaling pathways has proven successful. In this review, we aimed to outline the roles and regulatory mechanisms of PD-L1 in the properties of CSCs; the crosstalk between CSCs and immunosuppressive cells in TME, and recent progress and future promises of immunosuppression blockage to enhance CSC-targeted immunotherapy.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 4","pages":"1819-1836"},"PeriodicalIF":8.2,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11844285/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482949","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FBXW7 Directly Ubiquitinates and Degrades CTNNB1 Mediating the Suppression of ENKUR in Endometrial Cancer.","authors":"YaHui Liu, Qian Wang, QiRun Guo, Ying Zhu, Li Lin, ChunYan Yang, Bin Gong, Weiwei Yan, RenTao Hou, Yao Tang, XiuQiong Wu, Xinhui Liu, BeiXian Zhou, WeiYi Fang, LuYun Shu, SuiQun Guo","doi":"10.7150/ijbs.104067","DOIUrl":"10.7150/ijbs.104067","url":null,"abstract":"<p><p>Enkurin (ENKUR) is a tumor suppressor in some malignancies. However, its role in endometrial cancer (EC) remains unknown. Here, we firstly observed that reduced ENKUR expression promotes progression and poor prognosis in EC. Moreover,the overexpression of ENKUR suppressed the proliferation, migration, invasion, and intrahepatic dissemination of EC <i>in vitro</i> and <i>in vivo</i>. Repressing ENKUR expression by small-interfering RNA significantly reversed the inhibition of cell proliferation and invasion <i>in vitro</i>. We used co-immunoprecipitation combined with mass spectral analysis to identify the potential interactive proteins of ENKUR. Based on Gene Ontology analysis, we discovered that Wnt/β-catenin (Wnt/CTNNB1) signaling is a ENKUR-modulated key pathway. ENKUR binds to CTNNB1, significantly repressing its protein expression. Furthermore, ENKUR also binds to E3 ligase F-box and WD repeat domain containing 7 (FBXW7), a critical tumor suppressor. Interestingly, the latter binds to CTNNB1 and S502 of CTNNB1 is the key binding site, thereby increasing its protein ubiquitination and degradation. Finally, we confirmed that the predominant ubiquitination sites of CTNNB1 are located at K281 and K394. Transfection of ENKUR-overexpressing EC cells with CTNNB1 reversed the suppressive effects on tumor growth and invasion. ENKUR may be a tumor suppressor via recruiting FBXW7 to directly ubiquitinate and degrade CTNNB1 in EC.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 4","pages":"1801-1818"},"PeriodicalIF":8.2,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11844281/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of Parental Time-Restricted Feeding on Offspring Metabolic Phenotypic Traits.","authors":"Yibo Fan, Xiangyuan Peng, Nishat I Tabassum, Xiangru Cheng, Sharmelee Selvaraji, Vivian Tran, Tayla A Gibson Hughes, Buddhila Wickramasinghe, Abdulsatar Jamal, Quynh Nhu Dinh, Mathias Gelderblom, Grant R Drummond, Christopher G Sobey, Jim Penman, Terrance G Johns, Raghu Vemuganti, Jayantha Gunaratne, Mark P Mattson, Dong-Gyu Jo, Maria Jelinic, Thiruma V Arumugam","doi":"10.7150/ijbs.107469","DOIUrl":"10.7150/ijbs.107469","url":null,"abstract":"<p><p>Intermittent fasting (IF) is widely recognized for its numerous health benefits, yet its impact on metabolic health across generations remains relatively unexplored. This study investigates the intergenerational effects of parental IF, specifically through 8-hour daily time-restricted feeding, on the metabolic health of offspring. By examining four different combinations of parental mating groups, we demonstrate that parental IF can influence offspring metabolic health in distinct ways. Our results reveal that parental IF conferred significant metabolic advantages compared to ad libitum (AL) feeding. IF parents exhibited lower glucose, HbA1c, cholesterol, and CRP levels, and higher ketone levels compared to AL parents. Offspring of IF-exposed animals displayed sex-specific metabolic benefits when challenged with a high-fat, high-sugar, and high-salt (HFSS) diet. Notably, female offspring from IF parents were protected against HFSS-induced glucose intolerance and exhibited lower plasma glucose levels and higher ketone levels compared to offspring of ad libitum-fed parents. Additionally, female offspring from IF parents on a HFSS diet, along with both female and male offspring on a normal diet, had elevated plasma insulin levels. Furthermore, male offspring from IF parents on a normal diet exhibited a significant reduction in body weight compared to offspring from AL parents. These findings suggest that parental IF can impart enduring metabolic benefits to offspring and may serve as an effective strategy to mitigate the risks of obesity and diabetes in future generations.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 5","pages":"1852-1862"},"PeriodicalIF":8.2,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11900813/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting ALG3/FOXD1/BNIP3 Axis Prevents Mitophagy and Gemcitabine Resistance of Nasopharyngeal Carcinoma.","authors":"Zhanwang Wang, Yi Jin, Dong He, Yuxing Zhu, Mengqing Xiao, Xiaoming Liu, Yaxin Cheng, Ke Cao","doi":"10.7150/ijbs.101585","DOIUrl":"10.7150/ijbs.101585","url":null,"abstract":"<p><p>Understanding the specific role and underlying mechanisms of mitophagy may provide therapeutic benefit to patients with nasopharyngeal carcinoma (NPC). Forkhead box D1 (<i>FOXD1</i>), is overexpressed in NPC. However, its roles in NPC progression and therapy resistance remain largely unknown. NPC tissues displayed increased <i>FOXD1</i> expression compared to paired non-tumor tissues, which correlated with worse overall survival (OS). Upregulation of <i>FOXD1</i> promoted NPC cell proliferation, colony formation, migration, invasion, and impaired sensitivity to GEM by enhancing mitophagy levels. Mechanistically, <i>FOXD1</i> promoted mitophagy in NPC cells by transcriptionally initiating BNIP3 expression. This enhanced mitophagy, in turn, promoted proliferation, invasion, and migration and reduced NPC cell sensitivity to gemcitabine (GEM). Most interestingly, Asn176 <i>N</i>-glycosylation of the FOXD1 protein increased its stability and nuclear localization, thereby transcriptionally activating <i>BNIP3</i> expression to promote mitophagy of NPC cells. ALG3 directly interacted with FOXD1 and induced this <i>N</i>-glycosylation. Targeting the ALG3/FOXD1/BNIP3 axis offers a promising therapeutic strategy to inhibit the progression of NPC, which highlighting the potential of therapeutics targeting ALG3 and FOXD1 for regulating mitophagy and overcoming GEM resistance.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 5","pages":"1894-1913"},"PeriodicalIF":8.2,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11900802/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial Localization and Function of Adenosine Receptors.","authors":"Alejandro Sánchez-Melgar, Valentina Vultaggio-Poma, Simoneta Falzoni, Clara Fructuoso, José Luis Albasanz, Francesco Di Virgilio, Mairena Martín","doi":"10.7150/ijbs.101930","DOIUrl":"10.7150/ijbs.101930","url":null,"abstract":"<p><p>G-protein coupled receptors (GPCRs) are typically expressed on the cell surface where they mediate extracellular signals from hormones, neurotransmitters and growth factors, among others. However, growing evidence support the intracellular localization of GPCRs, including mitochondria. In the present work, we assessed the presence and functionality of adenosine receptors in mitochondria by combining techniques such as western blotting, radioligand binding, electron microscopy, enzymatic activities determination, oxygen consumption measurement and 3D morphological analysis of mitochondrial networks. Our results demonstrate the mitochondrial localization of adenosine A₁ and A₂ receptors in pure mitochondria fractions isolated from mouse brain and liver, human brain, HeLa and SH-SY5Y cells. Adenylyl cyclase activity assays revealed that these receptors are functional in the mitochondria. Moreover, exposure of isolated mitochondria to selective A₁, A_2A and A_2B receptors agonists revealed these receptors as potential modulators of mitochondrial energy metabolism, since ATP production and coupling efficiency increased in the presence of BAY 60-6583 (A_2B agonist) whereas proton leak and acute response were higher with CGS 21680 (A_2A agonist). Also, proton leak, ATP production, acute response and acute respiration were increased in the presence of CPA (A₁ agonist). Interestingly, different mitochondrial morphological changes were detected in HeLa cells exposed to these receptors' agonists.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 5","pages":"1874-1893"},"PeriodicalIF":8.2,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11900819/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}