Pub Date : 2025-07-01DOI: 10.1016/j.bbamcr.2025.120017
Yong Li , Yisong Qian , Evan Huang , Zain Schwarz , Hannah Tai , Katherine Tillock , Tianhua Lei , Xiaofeng Yang , Mingui Fu
It was recently reported that RNAs can be glycosylated, and such glycosylated RNAs (referred to as glycoRNAs) are located on the outer cell surface. We here reported that there are two forms of glycoRNAs, named as glycoRNA-L and glycoRNA-S, robustly expressed in human monocytes. We verified that the glycoRNA-S specifically detected in human monocytes is synthesized by enzyme-catalyzed conjugation, but not artificial products of labelling probe. RNase-treatment removed both glycoRNA-L and glycoRNA-S, suggesting that they are localized on cell surface. Removing glycoRNAs significantly suppressed the interaction of human monocytes with endothelial cells, suggesting that glycoRNAs mediate human monocyte adhesion. Using flow cytometry, immunoprecipitation and northern blotting we identified Siglec-5 as the binding receptor of glycoRNAs. Siglec-5 is expressed in human endothelial cells but presented on endothelial cell surface when endothelial cells are activated. We observed that glycoRNA-L was heavily labeled with sialic acid, whereas glycoRNA-S was heavily labeled with N-acetylgalactosamine and N-acetylglucosamine. Together, these results demonstrate that two forms of glycoRNAs exist in human monocytes, which may play significant role in controlling the interaction of human monocytes and endothelial cells and contribute to the pathogenesis of inflammatory diseases.
{"title":"GlycoRNA-L and glycoRNA-S mediate human monocyte adhesion via binding to Siglec-5","authors":"Yong Li , Yisong Qian , Evan Huang , Zain Schwarz , Hannah Tai , Katherine Tillock , Tianhua Lei , Xiaofeng Yang , Mingui Fu","doi":"10.1016/j.bbamcr.2025.120017","DOIUrl":"10.1016/j.bbamcr.2025.120017","url":null,"abstract":"<div><div>It was recently reported that RNAs can be glycosylated, <em>and</em> such glycosylated RNAs (referred to as glycoRNAs) are located on the outer cell surface. We here reported that there are two forms of glycoRNAs, named as glycoRNA-L and glycoRNA-S, robustly expressed in human monocytes. We verified that the glycoRNA-S specifically detected in human monocytes is synthesized by enzyme-catalyzed conjugation, but not artificial products of labelling probe. RNase-treatment removed both glycoRNA-L and glycoRNA-S, suggesting that they are localized on cell surface. Removing glycoRNAs significantly suppressed the interaction of human monocytes with endothelial cells, suggesting that glycoRNAs mediate human monocyte adhesion. Using flow cytometry, immunoprecipitation and northern blotting we identified Siglec-5 as the binding receptor of glycoRNAs. Siglec-5 is expressed in human endothelial cells but presented on endothelial cell surface when endothelial cells are activated. We observed that glycoRNA-L was heavily labeled with sialic acid, whereas glycoRNA-S was heavily labeled with <em>N</em>-acetylgalactosamine and <em>N</em>-acetylglucosamine. Together, these results demonstrate that two forms of glycoRNAs exist in human monocytes, which may play significant role in controlling the interaction of human monocytes and endothelial cells and contribute to the pathogenesis of inflammatory diseases.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 7","pages":"Article 120017"},"PeriodicalIF":4.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144534745","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}
Pub Date : 2025-06-30DOI: 10.1016/j.bbamcr.2025.120012
Qian Wang , Chang You , Xiaoning Qu , YiQing Zhang , Yuxiao Bai , Xianlong Lin , Zhaoxia Wang , Hezhi Fang , Jianxin Lyu , Minghua Jiang , Ya Wang
Mitochondrial disease caused by mitochondrial DNA (mtDNA) 3243A>G mutation is characterized by high levels of clinical heterogeneity. Varied m.3243A>G mutation loads among patients are used to, but cannot fully explain, disease heterogeneity. Here, we found that mtDNA genotypes (haplogroups) modify m.3243A>G-associated natural selection and cell fate determination. mtDNA haplogroup M7 was less prevalent in a multi-center m.3243A>G disease cohort. Further functional studies using cybrids showed that M7 accelerated cell proliferation and shortened G0/G1 cell cycle when compared with cybrid carrying a non-M7 haplogroup (D5). However, mitochondrial function and cell viability were even worse in M7 cybrid than D5 cybrid when treated with mitochondrial oxidative phosphorylation (OXPHOS) inhibitors, indicating that M7 drives negative selection in patients with m.3243A>G during evolution. By adopting multi-omics strategies, we showed a lesser increase of 15-hydroxyeicosatetraenoic acid (15-HETE) levels in M7 cybrid owing to OXPHOS inhibition, leading to insufficient Akt/FoxO1 activation and increased apoptosis. Notably, 15-HETE administration activated Akt/FoxO1 phosphorylation and abolished apoptosis difference between M7 and D5 cybrids, suggesting that augmented 15-HETE was vital to protect cells from death. Collectively, our work identified a genetic modifier of m.3243A>G-associated mitochondrial disease and demonstrated that the mitochondrial retrograde 15-HETE/Akt/FOXO1 signaling cascade plays an important role in protecting cells from OXPHOS dysfunction-induced cell death.
线粒体DNA (mtDNA) 3243 A > G突变引起的线粒体疾病具有高度的临床异质性。不同的m.3243 A > 患者之间的突变负荷习惯，但不能完全解释疾病的异质性。在这里，我们发现mtDNA基因型（单倍群）修饰m.3243 A > 与g相关的自然选择和细胞命运决定。mtDNA单倍群M7在多中心m.3243 a > G疾病队列中较少流行。进一步的功能研究表明，与携带非M7单倍群的杂交体相比，M7加速了细胞增殖，缩短了G0/G1细胞周期（D5）。然而，当线粒体氧化磷酸化（OXPHOS）抑制剂处理时，M7细胞系的线粒体功能和细胞活力甚至比D5细胞系更差，这表明M7在进化过程中驱动m.3243 A > G患者的负选择。采用多组学策略，我们发现由于OXPHOS抑制，M7杂交细胞中15-羟基二碳四烯酸（15-HETE）水平增加较少，导致Akt/FoxO1激活不足，细胞凋亡增加。值得注意的是，15-HETE激活了Akt/FoxO1磷酸化，并消除了M7和D5杂交体之间的凋亡差异，这表明15-HETE的增强对保护细胞免于死亡至关重要。总之，我们的工作确定了m.3243 a > g相关线粒体疾病的遗传修饰子，并证明线粒体逆行15-HETE/Akt/FOXO1信号级联在保护细胞免受OXPHOS功能障碍诱导的细胞死亡中起重要作用。
{"title":"Mitochondrial DNA genotypes modify m.3243A>G-associated mitochondrial disease via the 15-HETE/Akt/FoxO1 pathway","authors":"Qian Wang , Chang You , Xiaoning Qu , YiQing Zhang , Yuxiao Bai , Xianlong Lin , Zhaoxia Wang , Hezhi Fang , Jianxin Lyu , Minghua Jiang , Ya Wang","doi":"10.1016/j.bbamcr.2025.120012","DOIUrl":"10.1016/j.bbamcr.2025.120012","url":null,"abstract":"<div><div>Mitochondrial disease caused by mitochondrial DNA (mtDNA) 3243A>G mutation is characterized by high levels of clinical heterogeneity. Varied m.3243A>G mutation loads among patients are used to, but cannot fully explain, disease heterogeneity. Here, we found that mtDNA genotypes (haplogroups) modify m.3243A>G-associated natural selection and cell fate determination. mtDNA haplogroup M7 was less prevalent in a multi-center m.3243A>G disease cohort. Further functional studies using cybrids showed that M7 accelerated cell proliferation and shortened G0/G1 cell cycle when compared with cybrid carrying a non-M7 haplogroup (D5). However, mitochondrial function and cell viability were even worse in M7 cybrid than D5 cybrid when treated with mitochondrial oxidative phosphorylation (OXPHOS) inhibitors, indicating that M7 drives negative selection in patients with m.3243A>G during evolution. By adopting multi-omics strategies, we showed a lesser increase of 15-hydroxyeicosatetraenoic acid (15-HETE) levels in M7 cybrid owing to OXPHOS inhibition, leading to insufficient Akt/FoxO1 activation and increased apoptosis. Notably, 15-HETE administration activated Akt/FoxO1 phosphorylation and abolished apoptosis difference between M7 and D5 cybrids, suggesting that augmented 15-HETE was vital to protect cells from death. Collectively, our work identified a genetic modifier of m.3243A>G-associated mitochondrial disease and demonstrated that the mitochondrial retrograde 15-HETE/Akt/FOXO1 signaling cascade plays an important role in protecting cells from OXPHOS dysfunction-induced cell death.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 7","pages":"Article 120012"},"PeriodicalIF":4.6,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144551834","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}
Pub Date : 2025-06-28DOI: 10.1016/j.bbamcr.2025.120015
Lei Li , Peijing Ye , Guoping Li, Tao Xie, Chengpeng Zha, Zaihui Wang, Dongyan He, Chuanzheng Sun
We previously identified differentially expressed lncRNAs in carcinoma-associated fibroblasts (CAFs) using a lncRNA Chip. However, the molecular mechanisms by which CAFs-derived lncRNAs regulate radiotherapy resistance in Oral squamous cell carcinoma (OSCC) remain poorly understood. This study found that lncRNA RORA-AS1 (RORA-AS1) was markedly overexpressed in CAFs, exosomes derived from CAFs (CAFs-exo), and OSCC tissues. Notably, a RORA-AS1-based nomogram demonstrated robust predictive performance for OSCC patient survival. Moreover, RORA-AS1 showed a significant positive correlation with CAF infiltration. In in vitro experiments, both CAFs-CM and CAFs-exo enhanced Cal27 cell proliferation and upregulated RORA-AS1 and IFITM1 expression, while concurrently inhibiting apoptosis, upon exposure to 8 Gy X-rays irradiation. RORA-AS1 Knockdown mitigated the radiotherapy resistance induced by CAFs-exo in Cal27 cells. Mechanistically, RORA-AS1 knockdown led to increased expression of p-STAT1, p21, and p53, alongside decreased levels of p-STAT3 and IFITM1 in Cal27 cells. RIP assay confirmed the physical association between RORA-AS1 and the IFITM1 RNA complex. In in vivo experiments, CAFs-exo enhanced tumor growth and RORA-AS1 and IFITM1 expression under radiotherapy conditions, which was mitigated by RORA-AS1 knockdown. In conclusion, CAF-derived exosome RORA-AS1 facilitates radiotherapy resistance in OSCC by activating the IFITM1/STAT signaling cascade. These findings identify RORA-AS1 as a potential biomarker for the diagnosis and treatment of OSCC.
{"title":"Carcinoma-associated fibroblast-derived exosomes lncRNA RORA-AS1 facilitates radiotherapy resistance of oral squamous cell carcinoma through the IFITM1/STAT axis","authors":"Lei Li , Peijing Ye , Guoping Li, Tao Xie, Chengpeng Zha, Zaihui Wang, Dongyan He, Chuanzheng Sun","doi":"10.1016/j.bbamcr.2025.120015","DOIUrl":"10.1016/j.bbamcr.2025.120015","url":null,"abstract":"<div><div>We previously identified differentially expressed lncRNAs in carcinoma-associated fibroblasts (CAFs) using a lncRNA Chip. However, the molecular mechanisms by which CAFs-derived lncRNAs regulate radiotherapy resistance in Oral squamous cell carcinoma (OSCC) remain poorly understood. This study found that lncRNA RORA-AS1 (RORA-AS1) was markedly overexpressed in CAFs, exosomes derived from CAFs (CAFs-exo), and OSCC tissues. Notably, a RORA-AS1-based nomogram demonstrated robust predictive performance for OSCC patient survival. Moreover, RORA-AS1 showed a significant positive correlation with CAF infiltration. In in vitro experiments, both CAFs-CM and CAFs-exo enhanced Cal27 cell proliferation and upregulated RORA-AS1 and IFITM1 expression, while concurrently inhibiting apoptosis, upon exposure to 8 Gy X-rays irradiation. RORA-AS1 Knockdown mitigated the radiotherapy resistance induced by CAFs-exo in Cal27 cells. Mechanistically, RORA-AS1 knockdown led to increased expression of p-STAT1, p21, and p53, alongside decreased levels of p-STAT3 and IFITM1 in Cal27 cells. RIP assay confirmed the physical association between RORA-AS1 and the IFITM1 RNA complex. In in vivo experiments, CAFs-exo enhanced tumor growth and RORA-AS1 and IFITM1 expression under radiotherapy conditions, which was mitigated by RORA-AS1 knockdown. In conclusion, CAF-derived exosome RORA-AS1 facilitates radiotherapy resistance in OSCC by activating the IFITM1/STAT signaling cascade. These findings identify RORA-AS1 as a potential biomarker for the diagnosis and treatment of OSCC.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 7","pages":"Article 120015"},"PeriodicalIF":4.6,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144526317","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}
Pub Date : 2025-06-28DOI: 10.1016/j.bbamcr.2025.120013
Andrés Tittarelli , Kevin Calderón , María de los Ángeles Esveile , Antonia B. Abusleme , Mariana P. Arbat , Mauricio A. Retamal
Connexin (Cx) hemichannels have emerged as key regulators of both physiological and pathological processes. They exhibit a dual role in cellular function: while low-to-moderate activity supports cell-to-cell communication, excessive hemichannel opening can be detrimental, leading to cell death. In the context of cancer, the contribution of Cx hemichannels remains poorly defined. However, evidence from various models suggests that their activity may critically influence cancer progression. For example, Cx hemichannels mediate the release of signaling molecules such as ATP, which, upon conversion to adenosine, contributes to immunosuppression within the tumor microenvironment (TME). Notably, the activity of Cx hemichannels is modulated by several intracellular and extracellular factors—many of which are disrupted in tumors—suggesting that their regulatory dynamics in cancer may differ substantially from those under homeostatic conditions. This review aims to explore the potential roles of Cx hemichannels in shaping the TME, promoting immune evasion, and facilitating tumor progression. Given their putative relevance, future studies should focus on elucidating how cancer-associated alterations in regulatory mechanisms affect Cx hemichannel activity and whether such activity contributes to tumor aggressiveness. A clearer understanding of these processes may uncover novel therapeutic opportunities targeting Cx hemichannel regulation in oncology.
{"title":"Are connexin hemichannels playing any role in cancer?","authors":"Andrés Tittarelli , Kevin Calderón , María de los Ángeles Esveile , Antonia B. Abusleme , Mariana P. Arbat , Mauricio A. Retamal","doi":"10.1016/j.bbamcr.2025.120013","DOIUrl":"10.1016/j.bbamcr.2025.120013","url":null,"abstract":"<div><div>Connexin (Cx) hemichannels have emerged as key regulators of both physiological and pathological processes. They exhibit a dual role in cellular function: while low-to-moderate activity supports cell-to-cell communication, excessive hemichannel opening can be detrimental, leading to cell death. In the context of cancer, the contribution of Cx hemichannels remains poorly defined. However, evidence from various models suggests that their activity may critically influence cancer progression. For example, Cx hemichannels mediate the release of signaling molecules such as ATP, which, upon conversion to adenosine, contributes to immunosuppression within the tumor microenvironment (TME). Notably, the activity of Cx hemichannels is modulated by several intracellular and extracellular factors—many of which are disrupted in tumors—suggesting that their regulatory dynamics in cancer may differ substantially from those under homeostatic conditions. This review aims to explore the potential roles of Cx hemichannels in shaping the TME, promoting immune evasion, and facilitating tumor progression. Given their putative relevance, future studies should focus on elucidating how cancer-associated alterations in regulatory mechanisms affect Cx hemichannel activity and whether such activity contributes to tumor aggressiveness. A clearer understanding of these processes may uncover novel therapeutic opportunities targeting Cx hemichannel regulation in oncology.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 7","pages":"Article 120013"},"PeriodicalIF":4.6,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144513555","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}
Pub Date : 2025-06-28DOI: 10.1016/j.bbamcr.2025.120014
Ting Wei , Yuyan Lin , Wenhui Ouyang , Yu Lei , Xiali Yang , Linjie Chen , Xiaobai He , Quan Fang , Xiaoguang Zheng , Hang Tong , Binggang Tu , Jia Zeng , Jianxin Lyu , Miaomiao Du , Shanying Gui
MEGDHEL syndrome is a severe mitochondrial disorder caused by mutations in the SERAC1 gene, characterized by sensorineural deafness, encephalopathy, hepatopathy, and Leigh-like syndrome. A hallmark feature is neonatal liver failure, often leading to high mortality. There is currently no effective treatment. In this study, we used AAV9-SERAC1 gene therapy to address liver dysfunction and mitochondrial impairments in the Serac1−/− mouse model. Treatment with 4 × 1011 viral genomes led to improvements in liver histology, including reduced fatty degeneration and cholesterol accumulation, as well as enhanced mitochondrial morphology and function. Transmission electron microscopy revealed restored mitochondrial cristae and an increased number of mitochondria in treated mice. Respiratory complex showed activity recovery and mitochondrial DNA content was increased. Behavioral assessments also demonstrated significant improvements in motor coordination, with treated mice showing enhanced grasping strength and balance compared to controls. These findings suggest that AAV9-SERAC1 gene therapy can improve liver function and locomotor abilities in Serac1−/− mice, offering a promising therapeutic strategy for MEGDHEL syndrome.
{"title":"AAV9-mediated gene therapy restores liver function in the MEGDHEL mouse model","authors":"Ting Wei , Yuyan Lin , Wenhui Ouyang , Yu Lei , Xiali Yang , Linjie Chen , Xiaobai He , Quan Fang , Xiaoguang Zheng , Hang Tong , Binggang Tu , Jia Zeng , Jianxin Lyu , Miaomiao Du , Shanying Gui","doi":"10.1016/j.bbamcr.2025.120014","DOIUrl":"10.1016/j.bbamcr.2025.120014","url":null,"abstract":"<div><div>MEGDHEL syndrome is a severe mitochondrial disorder caused by mutations in the <em>SERAC1</em> gene, characterized by sensorineural deafness, encephalopathy, hepatopathy, and Leigh-like syndrome. A hallmark feature is neonatal liver failure, often leading to high mortality. There is currently no effective treatment. In this study, we used AAV9-SERAC1 gene therapy to address liver dysfunction and mitochondrial impairments in the <em>Serac1</em><sup><em>−</em></sup><em>/</em><sup><em>−</em></sup> mouse model. Treatment with 4 × 10<sup>11</sup> viral genomes led to improvements in liver histology, including reduced fatty degeneration and cholesterol accumulation, as well as enhanced mitochondrial morphology and function. Transmission electron microscopy revealed restored mitochondrial cristae and an increased number of mitochondria in treated mice. Respiratory complex showed activity recovery and mitochondrial DNA content was increased. Behavioral assessments also demonstrated significant improvements in motor coordination, with treated mice showing enhanced grasping strength and balance compared to controls. These findings suggest that AAV9-SERAC1 gene therapy can improve liver function and locomotor abilities in <em>Serac1</em><sup><em>−</em></sup><em>/</em><sup><em>−</em></sup> mice, offering a promising therapeutic strategy for MEGDHEL syndrome.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 7","pages":"Article 120014"},"PeriodicalIF":4.6,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144526316","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}
Pub Date : 2025-06-23DOI: 10.1016/j.bbamcr.2025.120011
Yan Hao , Bohan Li , Wendan Tian , Feiya Yin , Wei Liu
Myocardial infarction (MI) triggers a significant injury response that eventually leads to adverse cardiac remodeling and heart failure, with the extracellular matrix, including collagen, plays a crucial role in this process. However, the relationship between 5-methylcytosine (m5C) modification and cardiac remodeling after MI remains unclear. In this study, an MI model was established in mice through ligation of the left anterior descending coronary artery, and hypoxia-induced primary neonatal cardiac fibroblasts were used as a cell model. Various techniques, including bioinformatics, immunofluorescence, histopathology, Western blot, and in vivo adeno-associated virus (AAV) infection, were employed to investigate the role of Alyref in cardiac remodeling following MI. We found that the expression of the m5C reader Alyref was increased in infarcted myocardial tissue in mice. Single-cell sequencing data revealed that Alyref was most significantly expressed in activated cardiac fibroblasts after MI and was involved in regulating cardiac remodeling. RNA immunoprecipitation sequencing (RIP-seq) analysis indicated that Alyref modulates the synthesis of extracellular matrix proteins, including collagen and elastin, in cardiac fibroblasts. In hypoxia-induced primary cardiac fibroblasts, siRNA-mediated Alyref knockdown reduced the synthesis of Col1a2, Col3a1, and Eln, mechanistically linked to the inhibition of the Fbln1/Loxl1 pathway. Additionally, Alyref knockdown suppressed the proliferation and transdifferentiation of cardiac fibroblasts. In vivo, AAV-mediated Alyref silencing attenuated collagen/elastin synthesis, impairing cardiac remodeling and worsening cardiac function after MI in mice. Overall, our findings demonstrate that the m5C reader Alyref regulates extracellular matrix protein synthesis in cardiac fibroblasts and represents a potential therapeutic target for modulating cardiac remodeling after MI.
{"title":"The m5C reader Alyref regulates cardiac remodeling post-myocardial infarction by modulating extracellular matrix protein synthesis in cardiac fibroblasts","authors":"Yan Hao , Bohan Li , Wendan Tian , Feiya Yin , Wei Liu","doi":"10.1016/j.bbamcr.2025.120011","DOIUrl":"10.1016/j.bbamcr.2025.120011","url":null,"abstract":"<div><div>Myocardial infarction (MI) triggers a significant injury response that eventually leads to adverse cardiac remodeling and heart failure, with the extracellular matrix, including collagen, plays a crucial role in this process. However, the relationship between 5-methylcytosine (m5C) modification and cardiac remodeling after MI remains unclear. In this study, an MI model was established in mice through ligation of the left anterior descending coronary artery, and hypoxia-induced primary neonatal cardiac fibroblasts were used as a cell model. Various techniques, including bioinformatics, immunofluorescence, histopathology, Western blot, and in vivo adeno-associated virus (AAV) infection, were employed to investigate the role of Alyref in cardiac remodeling following MI. We found that the expression of the m5C reader Alyref was increased in infarcted myocardial tissue in mice. Single-cell sequencing data revealed that Alyref was most significantly expressed in activated cardiac fibroblasts after MI and was involved in regulating cardiac remodeling. RNA immunoprecipitation sequencing (RIP-seq) analysis indicated that Alyref modulates the synthesis of extracellular matrix proteins, including collagen and elastin, in cardiac fibroblasts. In hypoxia-induced primary cardiac fibroblasts, siRNA-mediated Alyref knockdown reduced the synthesis of Col1a2, Col3a1, and Eln, mechanistically linked to the inhibition of the Fbln1/Loxl1 pathway. Additionally, Alyref knockdown suppressed the proliferation and transdifferentiation of cardiac fibroblasts. In vivo, AAV-mediated Alyref silencing attenuated collagen/elastin synthesis, impairing cardiac remodeling and worsening cardiac function after MI in mice. Overall, our findings demonstrate that the m5C reader Alyref regulates extracellular matrix protein synthesis in cardiac fibroblasts and represents a potential therapeutic target for modulating cardiac remodeling after MI.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 7","pages":"Article 120011"},"PeriodicalIF":4.6,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144472197","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}
Pub Date : 2025-06-21DOI: 10.1016/j.bbamcr.2025.120010
Mélanie Robitaille , Michael H. McCullough , Choon Leng So , Sarah J. Roberts-Thomson , Gregory R. Monteith
Reduction in extracellular pH is common in pathophysiological conditions including neurological disorders, inflammation, and cancer. Like extracellular acidification, dysregulated calcium homeostasis is linked to various pathophysiological states including cancer. Changes in pH and calcium can theoretically be linked since the function of several calcium transporters is affected by pH changes. One such calcium channel is ORAI1, where changes in extracellular pH modulate gating.
Upon depletion of the endoplasmic reticulum (ER) calcium store, coupling of stromal interacting molecule 1 (STIM1) with ORAI1 facilitates calcium influx and refills the ER calcium store, a process known as Store-Operated Calcium Entry (SOCE). ORAI1 expression has been reported to be increased in several cancer types including basal breast cancer. The ORAI1 protein is expressed as two variants, ORAI1α (long) and ORAI1β (short). The differential roles of ORAI1α and ORAI1β are still not fully understood. Previous studies have shown that ORAI1 gating properties are affected by both intracellular and extracellular pH changes, but none have investigated whether ORAI1α and ORAI1β variants differ in sensitivity to pH changes.
In this study, we used cell-based calcium flux assays to compare ORAI1α- and ORAI1β-mediated calcium influx at different extracellular pHs. We developed a mathematical model of intracellular calcium dynamics incorporating SOCE to quantify variations in calcium influx. Fitting this model to our data revealed that at pH 6.8, ORAI1α is associated with more sustained calcium influx compared to ORAI1β. Point mutations in the N-terminus of ORAI1α identified potential domains responsible for the differential activation of ORAI1 variants at pH 6.8.
{"title":"ORAI1α and ORAI1β have differential sensitivity to extracellular pH","authors":"Mélanie Robitaille , Michael H. McCullough , Choon Leng So , Sarah J. Roberts-Thomson , Gregory R. Monteith","doi":"10.1016/j.bbamcr.2025.120010","DOIUrl":"10.1016/j.bbamcr.2025.120010","url":null,"abstract":"<div><div>Reduction in extracellular pH is common in pathophysiological conditions including neurological disorders, inflammation, and cancer. Like extracellular acidification, dysregulated calcium homeostasis is linked to various pathophysiological states including cancer. Changes in pH and calcium can theoretically be linked since the function of several calcium transporters is affected by pH changes. One such calcium channel is ORAI1, where changes in extracellular pH modulate gating.</div><div>Upon depletion of the endoplasmic reticulum (ER) calcium store, coupling of stromal interacting molecule 1 (STIM1) with ORAI1 facilitates calcium influx and refills the ER calcium store, a process known as Store-Operated Calcium Entry (SOCE). ORAI1 expression has been reported to be increased in several cancer types including basal breast cancer. The ORAI1 protein is expressed as two variants, ORAI1α (long) and ORAI1β (short). The differential roles of ORAI1α and ORAI1β are still not fully understood. Previous studies have shown that ORAI1 gating properties are affected by both intracellular and extracellular pH changes, but none have investigated whether ORAI1α and ORAI1β variants differ in sensitivity to pH changes.</div><div>In this study, we used cell-based calcium flux assays to compare ORAI1α- and ORAI1β-mediated calcium influx at different extracellular pHs. We developed a mathematical model of intracellular calcium dynamics incorporating SOCE to quantify variations in calcium influx. Fitting this model to our data revealed that at pH 6.8, ORAI1α is associated with more sustained calcium influx compared to ORAI1β. Point mutations in the N-terminus of ORAI1α identified potential domains responsible for the differential activation of ORAI1 variants at pH 6.8.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 7","pages":"Article 120010"},"PeriodicalIF":4.6,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144367848","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}
Pub Date : 2025-06-16DOI: 10.1016/j.bbamcr.2025.120009
Xuemei Zhang , Yadi Wang , Yujie Tang , Ran Wei, Runze Zhao, Zhenhai Yu, Chao Lu
Endometriosis (EM), a gynecologic disorder affecting 10 % of childbearing age women, with complex pathogenesis involving cell proliferation and metabolic abnormalities similar to malignancies. Unusual expression of key enzymes and regulators in glycolysis pathway contributes to the development of endometriosis. Phosphoglycerate kinase 1 (PGK1) was a key enzyme in glycolysis with additional roles as a transcription factor co-activator and protein kinase. We discovered that PGK1 was elevated and associated strongly with the development of EM. The PGK1 inhibitor NG52 inhibited the growth of endometriosis lesions in mice by preventing cell migration and proliferation. Furthermore, we found that DNA damage response 4 (DDIT4) was a new downstream target gene of PGK1. PGK1 regulated the nuclear translocation of DDIT4. Additionally, we also observed that PGK1 up-regulate the transcriptional activity of DDIT4, leading to DDIT4 overexpression that promoted the development of endometriosis. These findings may provide new insights for potential non-hormonal targeted therapies for endometriosis treatment.
{"title":"PGK1 mediates glycolysis and cell proliferation in endometriosis by regulating DDIT4 nuclear translocation","authors":"Xuemei Zhang , Yadi Wang , Yujie Tang , Ran Wei, Runze Zhao, Zhenhai Yu, Chao Lu","doi":"10.1016/j.bbamcr.2025.120009","DOIUrl":"10.1016/j.bbamcr.2025.120009","url":null,"abstract":"<div><div>Endometriosis (EM), a gynecologic disorder affecting 10 % of childbearing age women, with complex pathogenesis involving cell proliferation and metabolic abnormalities similar to malignancies. Unusual expression of key enzymes and regulators in glycolysis pathway contributes to the development of endometriosis. Phosphoglycerate kinase 1 (PGK1) was a key enzyme in glycolysis with additional roles as a transcription factor co-activator and protein kinase. We discovered that PGK1 was elevated and associated strongly with the development of EM. The PGK1 inhibitor NG52 inhibited the growth of endometriosis lesions in mice by preventing cell migration and proliferation. Furthermore, we found that DNA damage response 4 (DDIT4) was a new downstream target gene of PGK1. PGK1 regulated the nuclear translocation of DDIT4. Additionally, we also observed that PGK1 up-regulate the transcriptional activity of DDIT4, leading to DDIT4 overexpression that promoted the development of endometriosis. These findings may provide new insights for potential non-hormonal targeted therapies for endometriosis treatment.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 7","pages":"Article 120009"},"PeriodicalIF":4.6,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144322121","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}
Pub Date : 2025-06-13DOI: 10.1016/j.bbamcr.2025.120008
Shiwei Tu , Yanwei Li , Junyi Li , Ning Ma , Kaifang Yao , Zhihan Chen , Zezhi Fan , Zhifang Xu , Yuping Sa , Peng Jia , Xiaowei Lin , Shenjun Wang , Yuxin Fang , Yangyang Liu , Yi Guo
Mechanical forces are crucial in regulating fibroblast behavior, yet the underlying mechanisms remain unclear. This study aims to elucidate the role of the Piezo1 ion channel in fibroblast responses to mechanical stimulation. A mechanical stimulation culture platform was developed using a polydimethylsiloxane (PDMS)-based stretchable membrane and the Cell Tank uniaxial cell stretching system. Fibroblasts subjected to uniaxial cyclic stretching were analyzed using proteomic profiling, Western blotting, and confocal laser scanning microscopy to assess cytoskeletal changes and activation markers. Immunofluorescence staining was performed to evaluate the expression of Piezo1, YAP1, and Ki67 proteins. Cell viability and migration capacity were assessed using Calcein-AM/PI double staining and a migration assay. Mechanical stretch-induced fibroblast activation is characterized by morphological changes, increased proliferation, and enhanced migration. The cytoskeletal reorganization was observed, with elevated F-actin expression. Modulating Piezo1 activity altered fibroblast activation, indicating its essential role in mechanotransduction. These findings demonstrate that mechanical stretch upregulates Piezo1 expression, promoting fibroblast activation through the YAP pathway. This study provides new insights into the mechanotransduction mechanisms in fibroblasts and highlights the critical role of Piezo1 in mediating responses to mechanical stimuli, which may have implications for understanding tissue remodeling and fibrosis.
{"title":"Mechanical stretch-mediated fibroblast activation: The pivotal role of Piezo1 channels","authors":"Shiwei Tu , Yanwei Li , Junyi Li , Ning Ma , Kaifang Yao , Zhihan Chen , Zezhi Fan , Zhifang Xu , Yuping Sa , Peng Jia , Xiaowei Lin , Shenjun Wang , Yuxin Fang , Yangyang Liu , Yi Guo","doi":"10.1016/j.bbamcr.2025.120008","DOIUrl":"10.1016/j.bbamcr.2025.120008","url":null,"abstract":"<div><div>Mechanical forces are crucial in regulating fibroblast behavior, yet the underlying mechanisms remain unclear. This study aims to elucidate the role of the Piezo1 ion channel in fibroblast responses to mechanical stimulation. A mechanical stimulation culture platform was developed using a polydimethylsiloxane (PDMS)-based stretchable membrane and the Cell Tank uniaxial cell stretching system. Fibroblasts subjected to uniaxial cyclic stretching were analyzed using proteomic profiling, Western blotting, and confocal laser scanning microscopy to assess cytoskeletal changes and activation markers. Immunofluorescence staining was performed to evaluate the expression of Piezo1, YAP1, and Ki67 proteins. Cell viability and migration capacity were assessed using Calcein-AM/PI double staining and a migration assay. Mechanical stretch-induced fibroblast activation is characterized by morphological changes, increased proliferation, and enhanced migration. The cytoskeletal reorganization was observed, with elevated F-actin expression. Modulating Piezo1 activity altered fibroblast activation, indicating its essential role in mechanotransduction. These findings demonstrate that mechanical stretch upregulates Piezo1 expression, promoting fibroblast activation through the YAP pathway. This study provides new insights into the mechanotransduction mechanisms in fibroblasts and highlights the critical role of Piezo1 in mediating responses to mechanical stimuli, which may have implications for understanding tissue remodeling and fibrosis.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 7","pages":"Article 120008"},"PeriodicalIF":4.6,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144301116","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}
Hypoxia-inducible factors (HIFs) are master regulators of cellular adaptation to hypoxia in both disease and normal physiological conditions. HIFs consist of two subunits: the oxygen-sensitive alpha (α) and the constitutively expressed beta (β). The three oxygen-dependent alpha subunits—HIF-1α, HIF-2α, and HIF-3α—encoded by distinct genes are crucial for regulating cellular responses to hypoxia in various vertebrates, including humans. Much of our understanding of HIFs is based on studies on HIF-1α and HIF-2α subunits. Recent studies have shown that, although HIF-3α is the least studied member, it may also play essential roles in the development of human diseases, including cancer, cardiovascular and respiratory diseases, metabolic disorders, and other pathological processes. In this review, we focus on how HIF-3α overexpression is associated with various human diseases, aiming to better understand its role in human pathophysiology and its potential use as a therapeutic target.
{"title":"The role of hypoxia-inducible factor-3α in human disease","authors":"Alejandro López-Mejía, Paola Briseño-Díaz, Martha Robles-Flores","doi":"10.1016/j.bbamcr.2025.120007","DOIUrl":"10.1016/j.bbamcr.2025.120007","url":null,"abstract":"<div><div>Hypoxia-inducible factors (HIFs) are master regulators of cellular adaptation to hypoxia in both disease and normal physiological conditions. HIFs consist of two subunits: the oxygen-sensitive alpha (α) and the constitutively expressed beta (β). The three oxygen-dependent alpha subunits—HIF-1α, HIF-2α, and HIF-3α—encoded by distinct genes are crucial for regulating cellular responses to hypoxia in various vertebrates, including humans. Much of our understanding of HIFs is based on studies on HIF-1α and HIF-2α subunits. Recent studies have shown that, although HIF-3α is the least studied member, it may also play essential roles in the development of human diseases, including cancer, cardiovascular and respiratory diseases, metabolic disorders, and other pathological processes. In this review, we focus on how HIF-3α overexpression is associated with various human diseases, aiming to better understand its role in human pathophysiology and its potential use as a therapeutic target.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 7","pages":"Article 120007"},"PeriodicalIF":4.6,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144271097","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}
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