Pub Date : 2025-01-22DOI: 10.1016/j.bbamcr.2025.119903
Lu Wang , Na Li , Yang Chen, Yehua Qiao, Yaolin Song, Xiangyan Zhang, Han Zhao, Wenwen Ran, Guangqi Li, Xiaoming Xing
Among patients with colorectal cancer (CRC), metastasis accounts for the majority of deaths, and epithelial–mesenchymal transition (EMT) is important in the metastatic process. However, the mechanism underlying the correlation between the two in CRC is unknown. Here, we verified that a receptor-independent protein, G-protein signaling modulator 1 (GPSM1), was increased in CRC and had a significant positive correlation with matrix metalloproteinase 19 (MMP19). GPSM1 and MMP19 knockdown or overexpression decreased and increased proliferation, migration and invasion of CRC cells, respectively. In addition, overexpression or knockdown of GPSM1 and MMP19 upregulated and inhibited EMT, respectively. Interfering with MMP19 reversed EMT activation via GPSM1 overexpression. Apoptosis was induced by GPSM1 and MMP19 knockdown and activated the caspase3/Bcl-2/Bax signaling pathway. In conclusion, these results support the role of GPSM1 and MMP19 in CRC progression.
{"title":"GPSM1 interacts and cooperates with MMP19 to promote proliferation and EMT in colorectal cancer cells","authors":"Lu Wang , Na Li , Yang Chen, Yehua Qiao, Yaolin Song, Xiangyan Zhang, Han Zhao, Wenwen Ran, Guangqi Li, Xiaoming Xing","doi":"10.1016/j.bbamcr.2025.119903","DOIUrl":"10.1016/j.bbamcr.2025.119903","url":null,"abstract":"<div><div>Among patients with colorectal cancer (CRC), metastasis accounts for the majority of deaths, and epithelial–mesenchymal transition (EMT) is important in the metastatic process. However, the mechanism underlying the correlation between the two in CRC is unknown. Here, we verified that a receptor-independent protein, G-protein signaling modulator 1 (GPSM1), was increased in CRC and had a significant positive correlation with matrix metalloproteinase 19 (MMP19). GPSM1 and MMP19 knockdown or overexpression decreased and increased proliferation, migration and invasion of CRC cells, respectively. In addition, overexpression or knockdown of GPSM1 and MMP19 upregulated and inhibited EMT, respectively. Interfering with MMP19 reversed EMT activation via GPSM1 overexpression. Apoptosis was induced by GPSM1 and MMP19 knockdown and activated the caspase3/Bcl-2/Bax signaling pathway. In conclusion, these results support the role of GPSM1 and MMP19 in CRC progression.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119903"},"PeriodicalIF":4.6,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143036156","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 : 2025-01-19DOI: 10.1016/j.bbamcr.2025.119906
Francesca Inferrera , Ylenia Marino , Tiziana Genovese , Salvatore Cuzzocrea , Roberta Fusco , Rosanna Di Paola
Mitochondria play a key role in the regulation of energy homeostasis and ATP production in cardiac cells. Mitochondrial dysfunction can trigger several pathological events that contribute to the development and progression of cardiovascular diseases. These mechanisms include the induction of oxidative stress, dysregulation of intracellular calcium cycling, activation of the apoptotic pathway, and alteration of lipid metabolism. This review focuses on the role of mitochondria in intracellular signaling associated with cardiovascular diseases, emphasizing the contributions of reactive oxygen species production and mitochondrial dynamics. Indeed, mitochondrial dysfunction has been implicated in every aspect of cardiovascular disease and is currently being evaluated as a potential target for therapeutic interventions. To treat cardiovascular diseases and improve overall heart health, it is important to better understand these biochemical systems. These findings allow the achievement of targeted therapies and preventive measures. Therefore, this review investigates different studies that demonstrate how changes in mitochondrial dynamics like fusion, fission, and mitophagy contribute to the development or worsening of disorders related to heart diseases by summarizing current research on their role.
{"title":"Mitochondrial quality control: Biochemical mechanism of cardiovascular disease","authors":"Francesca Inferrera , Ylenia Marino , Tiziana Genovese , Salvatore Cuzzocrea , Roberta Fusco , Rosanna Di Paola","doi":"10.1016/j.bbamcr.2025.119906","DOIUrl":"10.1016/j.bbamcr.2025.119906","url":null,"abstract":"<div><div>Mitochondria play a key role in the regulation of energy homeostasis and ATP production in cardiac cells. Mitochondrial dysfunction can trigger several pathological events that contribute to the development and progression of cardiovascular diseases. These mechanisms include the induction of oxidative stress, dysregulation of intracellular calcium cycling, activation of the apoptotic pathway, and alteration of lipid metabolism. This review focuses on the role of mitochondria in intracellular signaling associated with cardiovascular diseases, emphasizing the contributions of reactive oxygen species production and mitochondrial dynamics. Indeed, mitochondrial dysfunction has been implicated in every aspect of cardiovascular disease and is currently being evaluated as a potential target for therapeutic interventions. To treat cardiovascular diseases and improve overall heart health, it is important to better understand these biochemical systems. These findings allow the achievement of targeted therapies and preventive measures. Therefore, this review investigates different studies that demonstrate how changes in mitochondrial dynamics like fusion, fission, and mitophagy contribute to the development or worsening of disorders related to heart diseases by summarizing current research on their role.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119906"},"PeriodicalIF":4.6,"publicationDate":"2025-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142999161","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}
Colorectal cancer (CRC) ranks second in mortality worldwide while metastasis accounts for most CRC-related deaths. Thus, understanding cell migration, a crucial step in metastasis, is imperative for developing new therapies. Growth Differentiation Factor-15 (GDF15), a member of the Transforming Growth Factor β superfamily, is overexpressed in CRC and promotes metastasis with a so far unknown mechanism. LIMS1 is a cell-matrix adhesion prosurvival protein that is also overexpressed in CRC and localized at the tumor invasive front, while bioinformatics analysis shows that both genes exhibit the same expression pattern in metastatic CRC samples. In the present study, treatment of low-aggressiveness HT29 CRC cells with human recombinant GDF15 (hrGDF15) led to increased LIMS1 expression, increased mRNA level of RhoGTPases RAC1 and RHOA but not CDC42, and increased migration. Conversely, GDF15 or LIMS1-siRNA-mediated silencing in invasive HCT116 cells resulted in downregulation of LIMS1 and GDF15 respectively, decreased RAC1, and RHOA as well as reduced cell migration, which were fully restored by hrGDF15 treatment both in GDF15 and LIMS1-siRNA-treated cells. Our findings indicate that GDF15 and LIMS1 have an interdependent role in the migration process which renders them potent targets for the development of novel therapeutic strategies to inhibit metastatic spread.
{"title":"Interdependent roles for growth differentiation factor-15 (GDF15) and LIMS1 in regulating cell migration: Implications for colorectal cancer metastasis","authors":"Andria Kotsoni , Louiza Valentina Kozaki , Andreas Stylianou , Vasiliki Gkretsi","doi":"10.1016/j.bbamcr.2025.119904","DOIUrl":"10.1016/j.bbamcr.2025.119904","url":null,"abstract":"<div><div>Colorectal cancer (CRC) ranks second in mortality worldwide while metastasis accounts for most CRC-related deaths. Thus, understanding cell migration, a crucial step in metastasis, is imperative for developing new therapies. Growth Differentiation Factor-15 (GDF15), a member of the Transforming Growth Factor β superfamily, is overexpressed in CRC and promotes metastasis with a so far unknown mechanism. LIMS1 is a cell-matrix adhesion prosurvival protein that is also overexpressed in CRC and localized at the tumor invasive front, while bioinformatics analysis shows that both genes exhibit the same expression pattern in metastatic CRC samples. In the present study, treatment of low-aggressiveness HT29 CRC cells with human recombinant GDF15 (hrGDF15) led to increased <em>LIMS1</em> expression, increased mRNA level of RhoGTPases <em>RAC1</em> and <em>RHOA</em> but not <em>CDC42,</em> and increased migration. Conversely, <em>GDF15</em> or <em>LIMS1-</em>siRNA-mediated silencing in invasive HCT116 cells resulted in downregulation of <em>LIMS1</em> and <em>GDF15</em> respectively, decreased <em>RAC1,</em> and <em>RHOA</em> as well as reduced cell migration, which were fully restored by hrGDF15 treatment both in <em>GDF15</em> and <em>LIMS1</em>-siRNA-treated cells<em>.</em> Our findings indicate that GDF15 and LIMS1 have an interdependent role in the migration process which renders them potent targets for the development of novel therapeutic strategies to inhibit metastatic spread.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119904"},"PeriodicalIF":4.6,"publicationDate":"2025-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142999047","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 : 2025-01-13DOI: 10.1016/j.bbamcr.2025.119902
Yongqi Yu , Bohao Zhao , Jiali Li , Jie Yang , Zhiyuan Bao , Jiawei Cai , Yang Chen , Xinsheng Wu
Dermal papilla cells (DPCs) are crucial for the growth and development of hair follicles (HF). (−)-Epigallocatechin-3-gallate (EGCG) is the primary catechin identified in green tea, which has antioxidant effects and regulates cell activity. This study demonstrates that EGCG could promote the proliferation of DPCs. In addition, EGCG treatment significantly upregulated the expression of PCNA, CCND1, HIF-1α, VEGFA, and Bcl-2 mRNAs in DPCs, while significantly reducing the gene expression of Bax. The optimal concentration of EGCG addition was screened. When detecting the antioxidant ability of DPCs, treatment with 0.5 μM EGCG could intensify the relative activity of catalase, superoxide dismutase, and glutathione, promoting the antioxidant ability and migration of DPCs. Subsequently, the differentially expressed genes (DEGs) associated with the EGCG treatment in DPCs were identified by RNA sequencing, revealing 21 DEGs, including VEGFA, POSTN, CLU, SERPINE2, and NPY. As the candidate gene, the role of VEGFA in regulating HF growth and development was investigated. Immunofluorescence staining revealed that EGCG treatment enhanced the fluorescence intensity of VEGFA and CLU in DPCs. After VEGFA overexpression and knockdown in DPCs, it was found to regulate the HF growth and the expression of development-related genes, enhance the expression of proliferating cell nuclear antigen, and promote DPCs proliferation. EGCG could also rescue the siRNA-VEGFA effect in DPCs. Thus, this study demonstrates that EGCG possibly regulates cell viability in DPCs by inducing VEGFA expression level, and provides a reference for exploring the mechanism of HF growth and the treatment of hair-related illnesses.
{"title":"(−)-Epigallocatechin-3-gallate promotes the dermal papilla cell proliferation and migration through the induction of VEGFA","authors":"Yongqi Yu , Bohao Zhao , Jiali Li , Jie Yang , Zhiyuan Bao , Jiawei Cai , Yang Chen , Xinsheng Wu","doi":"10.1016/j.bbamcr.2025.119902","DOIUrl":"10.1016/j.bbamcr.2025.119902","url":null,"abstract":"<div><div>Dermal papilla cells (DPCs) are crucial for the growth and development of hair follicles (HF). (−)-Epigallocatechin-3-gallate (EGCG) is the primary catechin identified in green tea, which has antioxidant effects and regulates cell activity. This study demonstrates that EGCG could promote the proliferation of DPCs. In addition, EGCG treatment significantly upregulated the expression of <em>PCNA</em>, <em>CCND1</em>, <em>HIF-1α</em>, <em>VEGFA</em>, and <em>Bcl-2</em> mRNAs in DPCs, while significantly reducing the gene expression of <em>Bax</em>. The optimal concentration of EGCG addition was screened. When detecting the antioxidant ability of DPCs, treatment with 0.5 μM EGCG could intensify the relative activity of catalase, superoxide dismutase, and glutathione, promoting the antioxidant ability and migration of DPCs. Subsequently, the differentially expressed genes (DEGs) associated with the EGCG treatment in DPCs were identified by RNA sequencing, revealing 21 DEGs, including <em>VEGFA</em>, <em>POSTN</em>, <em>CLU</em>, <em>SERPINE2</em>, and <em>NPY</em>. As the candidate gene, the role of <em>VEGFA</em> in regulating HF growth and development was investigated. Immunofluorescence staining revealed that EGCG treatment enhanced the fluorescence intensity of VEGFA and CLU in DPCs. After <em>VEGFA</em> overexpression and knockdown in DPCs, it was found to regulate the HF growth and the expression of development-related genes, enhance the expression of proliferating cell nuclear antigen, and promote DPCs proliferation. EGCG could also rescue the siRNA-<em>VEGFA</em> effect in DPCs. Thus, this study demonstrates that EGCG possibly regulates cell viability in DPCs by inducing <em>VEGFA</em> expression level, and provides a reference for exploring the mechanism of HF growth and the treatment of hair-related illnesses.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119902"},"PeriodicalIF":4.6,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998009","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}
Proteasome-dependent protein degradation and the digestion of peptides by aminopeptidases are essential for myogenesis. Methionine aminopeptidases (MetAPs) are uniquely involved in, both, the proteasomal degradation of proteins and in the regulation of translation (via involvement in post-translational modification). Suppressing MetAP1 and MetAP2 expression inhibits the myogenic differentiation of C2C12 myoblasts. However, the molecular mechanism by which inhibiting MetAPs impairs cellular function remains to be elucidated. Here, we provide evidence for our hypothesis that MetAPs regulate proteostasis and that their inhibition increases ER stress by disrupting the post-translational modification, and thereby compromises cell integrity. Thus, using C2C12 myoblasts, we investigate the effect of inhibiting MetAPs on cell proliferation and the molecular mechanisms underpinning its effects. We found that exposure to bengamide B (a MetAP inhibitor) caused C2C12 myoblasts to lose their proliferative abilities via cell cycle arrest. The underlying mechanism involved the accumulation of abnormal proteins (due to the decrease in the N-terminal methionine removal function) which led to increased endoplasmic reticulum stress, decreased protein synthesis, and a protective activation of the autophagy pathway. To identify the MetAP involved in these effects, we use siRNAs to specifically knockdown MetAP1 and MetAP2 expressions. We found that only MetAP2 knockdown mimicked the effects seen with bengamide B treatment. Thus, we suggest that MetAP2, rather than MetAP1, is involved in maintaining the integrity of C2C12 myoblasts. Our results are useful in understanding muscle regeneration, obesity, and overeating disorders. It will help guide new treatment strategies for these disorders.
{"title":"Inhibition of methionine aminopeptidase in C2C12 myoblasts disrupts cell integrity via increasing endoplasmic reticulum stress","authors":"Shion Osana , Cheng-Ta Tsai , Naoki Suzuki , Kazutaka Murayama , Masaki Kaneko , Katsuhiko Hata , Hiroaki Takada , Yutaka Kano , Ryoichi Nagatomi","doi":"10.1016/j.bbamcr.2025.119901","DOIUrl":"10.1016/j.bbamcr.2025.119901","url":null,"abstract":"<div><div>Proteasome-dependent protein degradation and the digestion of peptides by aminopeptidases are essential for myogenesis. Methionine aminopeptidases (MetAPs) are uniquely involved in, both, the proteasomal degradation of proteins and in the regulation of translation (via involvement in post-translational modification). Suppressing <em>MetAP1</em> and <em>MetAP2</em> expression inhibits the myogenic differentiation of C2C12 myoblasts. However, the molecular mechanism by which inhibiting MetAPs impairs cellular function remains to be elucidated. Here, we provide evidence for our hypothesis that MetAPs regulate proteostasis and that their inhibition increases ER stress by disrupting the post-translational modification, and thereby compromises cell integrity. Thus, using C2C12 myoblasts, we investigate the effect of inhibiting MetAPs on cell proliferation and the molecular mechanisms underpinning its effects. We found that exposure to bengamide B (a MetAP inhibitor) caused C2C12 myoblasts to lose their proliferative abilities via cell cycle arrest. The underlying mechanism involved the accumulation of abnormal proteins (due to the decrease in the N-terminal methionine removal function) which led to increased endoplasmic reticulum stress, decreased protein synthesis, and a protective activation of the autophagy pathway. To identify the MetAP involved in these effects, we use siRNAs to specifically knockdown <em>MetAP1</em> and <em>MetAP2</em> expressions. We found that only <em>MetAP2</em> knockdown mimicked the effects seen with bengamide B treatment. Thus, we suggest that MetAP2, rather than MetAP1, is involved in maintaining the integrity of C2C12 myoblasts. Our results are useful in understanding muscle regeneration, obesity, and overeating disorders. It will help guide new treatment strategies for these disorders.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119901"},"PeriodicalIF":4.6,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142999239","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}
Pub Date : 2025-01-10DOI: 10.1016/j.bbamcr.2025.119897
Georges Hraoui , Mélanie Grondin , Sophie Breton , Diana A. Averill-Bates
Hyperthermia is an adjuvant to chemotherapy and radiotherapy and sensitizes tumors to these treatments. However, repeated heat treatments result in acquisition of heat resistance (thermotolerance) in tumors. Thermotolerance is an adaptive survival response that appears to be mediated by upregulated cellular defenses. However, the mechanisms of activation remain unclear. When HeLa cells were exposed to mild heat shock at 40 °C for 3 h, levels of superoxide and peroxides increased. Cells were treated with mitochondrial antioxidant MitoQ and NADPH oxidase (NOX) inhibitor apocynin to characterize the contribution of these two sources to the total reactive oxygen species (ROS) pool. We found that both mitochondria and NOX are sources of ROS during mild heat shock at 40 °C. Heat-derived ROS are thought to activate the adaptive survival response at 40 °C. Nrf2, the master regulator of the cellular antioxidant response, is thought to play a pivotal role in establishing the adaptive survival response. Nrf2 was overexpressed or knocked down to assess its role. Moreover, Nrf2 levels correlate with the cellular redox state, and do so via scavenging of mitochondria- and NOX-derived ROS. Knockdown of Nrf2 markedly increased levels of ROS that were scavenged by either apocynin or MitoQ. Finally, critical defense proteins such as DJ-1 and PGAM5 seemed to require a two-key activation system mediated by Nrf2 and mitochondrial ROS. Our study characterized mitochondrial and NOX-derived ROS as being essential in activating cellular defenses alongside Nrf2 and underlines potential therapeutic targets that may contribute to the acquisition of thermotolerance.
{"title":"Nrf2 mediates mitochondrial and NADPH oxidase-derived ROS during mild heat stress at 40 °C","authors":"Georges Hraoui , Mélanie Grondin , Sophie Breton , Diana A. Averill-Bates","doi":"10.1016/j.bbamcr.2025.119897","DOIUrl":"10.1016/j.bbamcr.2025.119897","url":null,"abstract":"<div><div>Hyperthermia is an adjuvant to chemotherapy and radiotherapy and sensitizes tumors to these treatments. However, repeated heat treatments result in acquisition of heat resistance (thermotolerance) in tumors. Thermotolerance is an adaptive survival response that appears to be mediated by upregulated cellular defenses. However, the mechanisms of activation remain unclear. When HeLa cells were exposed to mild heat shock at 40 °C for 3 h, levels of superoxide and peroxides increased. Cells were treated with mitochondrial antioxidant MitoQ and NADPH oxidase (NOX) inhibitor apocynin to characterize the contribution of these two sources to the total reactive oxygen species (ROS) pool. We found that both mitochondria and NOX are sources of ROS during mild heat shock at 40 °C. Heat-derived ROS are thought to activate the adaptive survival response at 40 °C. Nrf2, the master regulator of the cellular antioxidant response, is thought to play a pivotal role in establishing the adaptive survival response. Nrf2 was overexpressed or knocked down to assess its role. Moreover, Nrf2 levels correlate with the cellular redox state, and do so via scavenging of mitochondria- and NOX-derived ROS. Knockdown of Nrf2 markedly increased levels of ROS that were scavenged by either apocynin or MitoQ. Finally, critical defense proteins such as DJ-1 and PGAM5 seemed to require a two-key activation system mediated by Nrf2 and mitochondrial ROS. Our study characterized mitochondrial and NOX-derived ROS as being essential in activating cellular defenses alongside Nrf2 and underlines potential therapeutic targets that may contribute to the acquisition of thermotolerance.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119897"},"PeriodicalIF":4.6,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142969535","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 : 2025-01-09DOI: 10.1016/j.bbamcr.2025.119899
Ayda Tavitian , Elad Lax , Wei Song , Moshe Szyf , Hyman M. Schipper
Schizophrenia is a complex neuropsychiatric disorder featuring enhanced brain oxidative stress and deficient reelin protein. GFAP.HMOX10-12m mice that overexpress heme oxygenase-1 (HO-1) in astrocytes manifest a schizophrenia-like neurochemical, neuropathological and behavioral phenotype including brain oxidative stress and reelin downregulation. We used RT-PCR, targeted bisulfite next-generation sequencing, immunohistochemistry and in situ hybridization on hippocampal tissue of GFAP.HMOX10-12m mice to delineate a possible molecular mechanism for the downregulation of reelin and to identify the neuronal and non-neuronal (glial) cell types expressing reelin in our model. We found reduced reelin and increased DNMT1 and TET1 mRNA expression in the hippocampus of male GFAP.HMOX10-12m mice and reduced GAD67 mRNA expression in females. These mRNA changes were accompanied by sexually dimorphic alterations in DNA methylation levels of Reln and Gad1 genes. Reelin protein was expressed by oligodendrocytes and GABAergic interneurons, but not by astrocytes or microglia in GFAP.HMOX10-12m and wild-type brains of both sexes. Reelin mRNA was also observed in oligodendrocytes. Moreover, a significant downregulation of reelin-expressing oligodendrocytes was detected in the hippocampal dentate gyrus of male GFAP.HMOX10-12m mice. These results suggest a novel mechanism for brain reelin depletion in schizophrenia. Containment of the astrocytic HO-1 cascade by pharmacological or other means may protect against stress-induced brain reelin depletion in schizophrenia and other neurodevelopmental disorders.
{"title":"Hippocampal reelin and GAD67 gene expression and methylation in the GFAP.HMOX1 mouse model of schizophrenia","authors":"Ayda Tavitian , Elad Lax , Wei Song , Moshe Szyf , Hyman M. Schipper","doi":"10.1016/j.bbamcr.2025.119899","DOIUrl":"10.1016/j.bbamcr.2025.119899","url":null,"abstract":"<div><div>Schizophrenia is a complex neuropsychiatric disorder featuring enhanced brain oxidative stress and deficient reelin protein. GFAP.HMOX1<sup>0-12m</sup> mice that overexpress heme oxygenase-1 (HO-1) in astrocytes manifest a schizophrenia-like neurochemical, neuropathological and behavioral phenotype including brain oxidative stress and reelin downregulation. We used RT-PCR, targeted bisulfite next-generation sequencing, immunohistochemistry and <em>in situ</em> hybridization on hippocampal tissue of GFAP.HMOX1<sup>0-12m</sup> mice to delineate a possible molecular mechanism for the downregulation of reelin and to identify the neuronal and non-neuronal (glial) cell types expressing reelin in our model. We found reduced reelin and increased DNMT1 and TET1 mRNA expression in the hippocampus of male GFAP.HMOX1<sup>0-12m</sup> mice and reduced GAD67 mRNA expression in females. These mRNA changes were accompanied by sexually dimorphic alterations in DNA methylation levels of <em>Reln</em> and <em>Gad1</em> genes. Reelin protein was expressed by oligodendrocytes and GABAergic interneurons, but not by astrocytes or microglia in GFAP.HMOX1<sup>0-12m</sup> and wild-type brains of both sexes. Reelin mRNA was also observed in oligodendrocytes. Moreover, a significant downregulation of reelin-expressing oligodendrocytes was detected in the hippocampal dentate gyrus of male GFAP.HMOX1<sup>0-12m</sup> mice. These results suggest a novel mechanism for brain reelin depletion in schizophrenia. Containment of the astrocytic HO-1 cascade by pharmacological or other means may protect against stress-induced brain reelin depletion in schizophrenia and other neurodevelopmental disorders.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119899"},"PeriodicalIF":4.6,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142969534","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}
Pub Date : 2025-01-07DOI: 10.1016/j.bbamcr.2025.119896
Mai Khanh Linh Nguyen , Céline Pinkenburg , Jonathan James Du , Marc Bernaus-Esqué , Carlos Enrich , Carles Rentero , Thomas Grewal
Cholesterol is an essential lipid that ensures the functional integrity of mammalian cells. Most cells acquire cholesterol via endocytosis of low-density lipoproteins (LDL). Upon reaching late endosomes/lysosomes (LE/Lys), incoming ligands, including LDL-derived cholesterol, are distributed to other organelles. Niemann-Pick Type C1/2 (NPC1/2) proteins, members of the steroidogenic acute regulatory-related lipid transfer domain (StARD) and oxysterol-binding protein (OSBP) families facilitate the cellular distribution of cholesterol. NPC disease, a rare neurodegenerative disorder characterized by LE/Lys-cholesterol accumulation due to loss-of-function NPC1/2 mutations, underscores the physiological importance of LE/Lys-cholesterol distribution. Several Rab-GTPase family members, which play fundamental roles in directional membrane and lipid transport, including Rab7, 8 and 9, are critical for the delivery of cholesterol from LE/Lys to other organelles along vesicular and non-vesicular pathways. The insights gained from these regulatory circuits provide a foundation for the development of therapeutic strategies that could effectively address the cellular pathogenesis triggered by NPC1 deficiency and other lysosomal storage disorders.
胆固醇是确保哺乳动物细胞功能完整的必需脂质。大多数细胞通过内吞低密度脂蛋白（LDL）获得胆固醇。到达晚期内体/溶酶体（LE/Lys）后，进入的配体，包括低密度脂蛋白衍生的胆固醇，被分配到其他细胞器。Niemann-Pick Type C1/2 （NPC1/2）蛋白是甾体源性急性调节相关脂质转移域（standard）和氧甾醇结合蛋白（OSBP）家族的成员，促进胆固醇的细胞分布。NPC疾病是一种罕见的神经退行性疾病，其特征是由于NPC1/2突变丧失功能而导致LE/ lys -胆固醇积累，强调了LE/ lys -胆固醇分布的生理重要性。Rab7、rab8和rab9等Rab7 - gtpase家族成员在定向膜和脂质运输中起着重要作用，它们对于胆固醇沿着囊泡和非囊泡途径从LE/Lys传递到其他细胞器至关重要。从这些调控回路中获得的见解为开发治疗策略提供了基础，这些策略可以有效地解决由NPC1缺陷和其他溶酶体储存疾病引发的细胞发病机制。
{"title":"The multiple facets of Rab proteins modulating the cellular distribution of cholesterol from the late endosomal compartment","authors":"Mai Khanh Linh Nguyen , Céline Pinkenburg , Jonathan James Du , Marc Bernaus-Esqué , Carlos Enrich , Carles Rentero , Thomas Grewal","doi":"10.1016/j.bbamcr.2025.119896","DOIUrl":"10.1016/j.bbamcr.2025.119896","url":null,"abstract":"<div><div>Cholesterol is an essential lipid that ensures the functional integrity of mammalian cells. Most cells acquire cholesterol via endocytosis of low-density lipoproteins (LDL). Upon reaching late endosomes/lysosomes (LE/Lys), incoming ligands, including LDL-derived cholesterol, are distributed to other organelles. Niemann-Pick Type C1/2 (NPC1/2) proteins, members of the steroidogenic acute regulatory-related lipid transfer domain (StARD) and oxysterol-binding protein (OSBP) families facilitate the cellular distribution of cholesterol. NPC disease, a rare neurodegenerative disorder characterized by LE/Lys-cholesterol accumulation due to loss-of-function NPC1/2 mutations, underscores the physiological importance of LE/Lys-cholesterol distribution. Several Rab-GTPase family members, which play fundamental roles in directional membrane and lipid transport, including Rab7, 8 and 9, are critical for the delivery of cholesterol from LE/Lys to other organelles along vesicular and non-vesicular pathways. The insights gained from these regulatory circuits provide a foundation for the development of therapeutic strategies that could effectively address the cellular pathogenesis triggered by NPC1 deficiency and other lysosomal storage disorders.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119896"},"PeriodicalIF":4.6,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142943532","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}
Pub Date : 2025-01-06DOI: 10.1016/j.bbamcr.2025.119898
Tae-Uk Kwon , Yeo-Jung Kwon , Hyemin Park , Hyein Lee , Ji-Heung Kwak , Keon Wook Kang , Young-Jin Chun
X-linked ichthyosis (XLI) is a genetic disorder characterized by a steroid sulfatase (STS) deficiency inducing excessive cholesterol sulfate accumulation and keratinization. Our study utilizes STS knockout mice to reproduce the hyperkeratinization typical of XLI, providing a valuable model for investigating the underlying mechanisms. From the experiment of STS-deficient keratinocytes using the CRISPR/Cas9 system, we observed upregulation of E-cadherin, which is associated with keratinocyte differentiation and stratification. This was accompanied by elevated levels of keratinization markers, including involucrin and loricrin. We also found an increased expression of SULT2B1, which converts cholesterol to cholesterol sulfate, further accelerating cholesterol sulfate accumulation. As a result, STS deficiency and cholesterol sulfate accumulation lead to decreased expression of Hakai, the ubiquitin E3 ligase for E-cadherin. With reduced Hakai, endocytosis and ubiquitin-mediated degradation of E-cadherin are inhibited, resulting in its stabilization. This stabilization of E-cadherin is accompanied by increased expression of involucrin and loricrin, which is suppressed when the N-terminal extracellular domain of E-cadherin, responsible for cell-cell adhesion, is genetically modified. We propose that inhibition of E-cadherin, genetic modification of the N-terminal extracellular domain, and treatment with miR-6766 targeting E-cadherin significantly reduce the expression of keratinization markers, suggesting a potential therapeutic approach. We further suggest that the increased expression of E-cadherin observed in keratinocytes with STS deficiency is regulated by Hakai, underscoring the central role of E-cadherin in the pathogenesis of XLI.
{"title":"Steroid sulfatase suppresses keratinization by inducing proteasomal degradation of E-cadherin via Hakai regulation","authors":"Tae-Uk Kwon , Yeo-Jung Kwon , Hyemin Park , Hyein Lee , Ji-Heung Kwak , Keon Wook Kang , Young-Jin Chun","doi":"10.1016/j.bbamcr.2025.119898","DOIUrl":"10.1016/j.bbamcr.2025.119898","url":null,"abstract":"<div><div>X-linked ichthyosis (XLI) is a genetic disorder characterized by a steroid sulfatase (STS) deficiency inducing excessive cholesterol sulfate accumulation and keratinization. Our study utilizes STS knockout mice to reproduce the hyperkeratinization typical of XLI, providing a valuable model for investigating the underlying mechanisms. From the experiment of STS-deficient keratinocytes using the CRISPR/Cas9 system, we observed upregulation of E-cadherin, which is associated with keratinocyte differentiation and stratification. This was accompanied by elevated levels of keratinization markers, including involucrin and loricrin. We also found an increased expression of SULT2B1, which converts cholesterol to cholesterol sulfate, further accelerating cholesterol sulfate accumulation. As a result, STS deficiency and cholesterol sulfate accumulation lead to decreased expression of Hakai, the ubiquitin E3 ligase for E-cadherin. With reduced Hakai, endocytosis and ubiquitin-mediated degradation of E-cadherin are inhibited, resulting in its stabilization. This stabilization of E-cadherin is accompanied by increased expression of involucrin and loricrin, which is suppressed when the N-terminal extracellular domain of E-cadherin, responsible for cell-cell adhesion, is genetically modified. We propose that inhibition of E-cadherin, genetic modification of the N-terminal extracellular domain, and treatment with miR-6766 targeting E-cadherin significantly reduce the expression of keratinization markers, suggesting a potential therapeutic approach. We further suggest that the increased expression of E-cadherin observed in keratinocytes with STS deficiency is regulated by Hakai, underscoring the central role of E-cadherin in the pathogenesis of XLI.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119898"},"PeriodicalIF":4.6,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143164818","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}
Pub Date : 2025-01-05DOI: 10.1016/j.bbamcr.2025.119900
Martin Hirtl , Benjamin Gottschalk , Olaf A. Bachkoenig , Furkan E. Oflaz , Corina Madreiter-Sokolowski , Morten Andre Høydal , Wolfgang F. Graier
The uptake of Ca2+ by mitochondria is an important and tightly controlled process in various tissues. Even small changes in the key proteins involved in this process can lead to significant cellular dysfunction and, ultimately, cell death. In this study, we used stimulated emission depletion (STED) microscopy and developed an unbiased approach to monitor the sub-mitochondrial distribution and dynamics of the mitochondrial calcium uniporter (MCU) and mitochondrial calcium uptake 1 (MICU1) under resting and stimulated conditions. To visualize the inner mitochondrial membrane, the STED-optimized dye called pkMitoRed was used. The study presented herein builds on the previously verified exclusive localization of MICU1 in the intermembrane space, and that MCU moves exclusively laterally along the inner mitochondrial membrane (IMM). We applied a multi-angled arrow histogram to analyze the distribution of proteins within mitochondria, providing a one-dimensional view of protein localization along a defined distance. Combining this with optimal transport colocalization enabled us to further predict submitochondrial protein distribution. Results indicate that in HeLa cells Ca2+ elevation yielded MCU translocation from the cristae membrane (CM) to the inner boundary membrane (IBM). In AC16 cardiomyocyte cell line, MCU is mainly located at the IBM under resting conditions, and it translocates to the CM upon rising Ca2+. Our data describe a novel unbiased super-resolution image analysis approach. Our showcase sheds light on differences in spatial distribution dynamics of MCU in cell lines with different MICU1:MCU abundance.
{"title":"A novel super-resolution STED microscopy analysis approach to observe spatial MCU and MICU1 distribution dynamics in cells","authors":"Martin Hirtl , Benjamin Gottschalk , Olaf A. Bachkoenig , Furkan E. Oflaz , Corina Madreiter-Sokolowski , Morten Andre Høydal , Wolfgang F. Graier","doi":"10.1016/j.bbamcr.2025.119900","DOIUrl":"10.1016/j.bbamcr.2025.119900","url":null,"abstract":"<div><div>The uptake of Ca<sup>2+</sup> by mitochondria is an important and tightly controlled process in various tissues. Even small changes in the key proteins involved in this process can lead to significant cellular dysfunction and, ultimately, cell death. In this study, we used stimulated emission depletion (STED) microscopy and developed an unbiased approach to monitor the sub-mitochondrial distribution and dynamics of the mitochondrial calcium uniporter (MCU) and mitochondrial calcium uptake 1 (MICU1) under resting and stimulated conditions. To visualize the inner mitochondrial membrane, the STED-optimized dye called pkMitoRed was used. The study presented herein builds on the previously verified exclusive localization of MICU1 in the intermembrane space, and that MCU moves exclusively laterally along the inner mitochondrial membrane (IMM). We applied a multi-angled arrow histogram to analyze the distribution of proteins within mitochondria, providing a one-dimensional view of protein localization along a defined distance. Combining this with optimal transport colocalization enabled us to further predict submitochondrial protein distribution. Results indicate that in HeLa cells Ca<sup>2+</sup> elevation yielded MCU translocation from the cristae membrane (CM) to the inner boundary membrane (IBM). In AC16 cardiomyocyte cell line, MCU is mainly located at the IBM under resting conditions, and it translocates to the CM upon rising Ca<sup>2+</sup>. Our data describe a novel unbiased super-resolution image analysis approach. Our showcase sheds light on differences in spatial distribution dynamics of MCU in cell lines with different MICU1:MCU abundance.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119900"},"PeriodicalIF":4.6,"publicationDate":"2025-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142963656","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}
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