Biochimica et biophysica acta. Molecular cell research最新文献_第5页

H2S inhibition of xanthine dehydrogenase to xanthine oxidase conversion reduces uric acid levels and improves myoblast functions

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-01-27 DOI: 10.1016/j.bbamcr.2025.119909

Joshua MacNeil , Yuehong Wang , Guangdong Yang

Hydrogen sulfide (H₂S) is an important gasotransmitter that regulates a wide range of pathophysiological processes. Higher uric acid levels are associated with an increased risk of metabolic diseases. The causal mechanism linking H₂S signalling and uric acid metabolism in skeletal muscles has not yet been elucidated. This study aimed to explore the intertwined metabolisms of H₂S and uric acid as well as their integrated roles in controlling myoblast cell functions. It was first found that purine overload increased uric acid levels, promoted oxidative stress, mitochondrial damage, and apoptosis in cultured mouse myoblasts, which could be reversed by the exogenously application of H₂S at physiologically relevant concentration. In addition, H₂S significantly inhibited the expressions of inflammatory genes (encoding IL2, IL4, and TNFα) but had no effect on oxidative stress, mitochondrial damage and cell death induced by excessive uric acid. Mechanistically, H₂S inhibited xanthine oxidoreductase (XOR) activity by blocking the conversion of xanthine dehydrogenase (XDH) to xanthine oxidase (XO), thus reducing uric acid levels and improving myoblast functions. In addition, purine and uric acid attenuated the expression of cystathionine gamma-lyase (CSE, an H₂S-generating enzyme) and suppressed endogenous H₂S production. Blood uric acid levels and skeletal muscle XOR activity were significantly higher in CSE knockout mice than in wild-type mice. This study revealed a mutual interaction between H₂S signalling and uric acid metabolism in the regulation myoblast functions. Thus, the CSE/H₂S system may be a target for the prevention of hyperuricemia-related metabolic syndromes.

{"title":"H2S inhibition of xanthine dehydrogenase to xanthine oxidase conversion reduces uric acid levels and improves myoblast functions","authors":"Joshua MacNeil , Yuehong Wang , Guangdong Yang","doi":"10.1016/j.bbamcr.2025.119909","DOIUrl":"10.1016/j.bbamcr.2025.119909","url":null,"abstract":"<div><div>Hydrogen sulfide (H<sub>2</sub>S) is an important gasotransmitter that regulates a wide range of pathophysiological processes. Higher uric acid levels are associated with an increased risk of metabolic diseases. The causal mechanism linking H<sub>2</sub>S signalling and uric acid metabolism in skeletal muscles has not yet been elucidated. This study aimed to explore the intertwined metabolisms of H<sub>2</sub>S and uric acid as well as their integrated roles in controlling myoblast cell functions. It was first found that purine overload increased uric acid levels, promoted oxidative stress, mitochondrial damage, and apoptosis in cultured mouse myoblasts, which could be reversed by the exogenously application of H<sub>2</sub>S at physiologically relevant concentration. In addition, H<sub>2</sub>S significantly inhibited the expressions of inflammatory genes (encoding IL2, IL4, and TNFα) but had no effect on oxidative stress, mitochondrial damage and cell death induced by excessive uric acid. Mechanistically, H<sub>2</sub>S inhibited xanthine oxidoreductase (XOR) activity by blocking the conversion of xanthine dehydrogenase (XDH) to xanthine oxidase (XO), thus reducing uric acid levels and improving myoblast functions. In addition, purine and uric acid attenuated the expression of cystathionine gamma-lyase (CSE, an H<sub>2</sub>S-generating enzyme) and suppressed endogenous H<sub>2</sub>S production. Blood uric acid levels and skeletal muscle XOR activity were significantly higher in CSE knockout mice than in wild-type mice. This study revealed a mutual interaction between H<sub>2</sub>S signalling and uric acid metabolism in the regulation myoblast functions. Thus, the CSE/H<sub>2</sub>S system may be a target for the prevention of hyperuricemia-related metabolic syndromes.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119909"},"PeriodicalIF":4.6,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063462","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}

引用次数: 0

MARCH5 ameliorates aortic valve calcification via RACGAP1-DRP1 associated mitochondrial quality control

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-01-27 DOI: 10.1016/j.bbamcr.2025.119911

Jialiang Zhang , Yaoyu Zhang , Wenhua Lei , Jing Zhou , Yanjiani Xu , Zhou Hao , Yanbiao Liao , Fangyang Huang , Mao Chen

Background

Mitochondrial E3 ubiquitin ligase (MARCH5) as an important regulator in maintaining mitochondrial function. Our aims were to investigate the role and mechanism of MARCH5 in aortic valve calcification.

Methods

Human aortic valves, both calcified and non-calcified, were analyzed for MARCH5 expression using western blotting. Mitochondrial fragmentation was evaluated using transmission electron microscope. Osteogenic differentiation of human aortic valvular interstitial cells (HVICs) was induced with osteoblastic medium (OM), confirmed by western blotting and Alizarin red staining. Mitochondrial morphology and oxidative phosphorylation were assessed using MitoTracker and Seahorse, respectively. MARCH5-knockdown and ApoE-knockout mice fed high-fat diet were used to study aortic valve calcification.

Results

The mitochondrial quality control was impaired in calcified valves, and the level of MARCH5 protein was also decreased in calcified valves. Inhibition of MARCH5 impaired mitochondrial quality control, increased mitochondrial stress and accelerates osteogenic transformation in OM treated HVICs. While, overexpression MARCH5 has the opposite effects. Co-immunoprecipitation, mass spectrometry and molecular docking found MARCH5 interacted Rac GTPase-activating protein 1 (RACGAP1) and promoted its ubiquitination, leading to impaired mitochondrial quality control. Inhibiting RACGAP1 reversed osteogenic transformation induced by MARCH5 silencing in OM treated HVICs. Silencing dynamin-related protein 1 (DRP1) under RACGAP1 inhibition had no additional benefit. In vivo, deficiency of MARCH5 promoted aortic valve calcification, while inhibition RACGAP1 reversed aortic valve calcification in MARCH5 deficiency mice.

Conclusion

Downregulation of MARCH5 promotes RACGAP1 ubiquitination, activating DRP1 and impairing mitochondrial quality control, which contributes to aortic valve calcification. This identifies a potential therapeutic target for aortic valve calcification.

{"title":"MARCH5 ameliorates aortic valve calcification via RACGAP1-DRP1 associated mitochondrial quality control","authors":"Jialiang Zhang , Yaoyu Zhang , Wenhua Lei , Jing Zhou , Yanjiani Xu , Zhou Hao , Yanbiao Liao , Fangyang Huang , Mao Chen","doi":"10.1016/j.bbamcr.2025.119911","DOIUrl":"10.1016/j.bbamcr.2025.119911","url":null,"abstract":"<div><h3>Background</h3><div>Mitochondrial E3 ubiquitin ligase (MARCH5) as an important regulator in maintaining mitochondrial function. Our aims were to investigate the role and mechanism of MARCH5 in aortic valve calcification.</div></div><div><h3>Methods</h3><div>Human aortic valves, both calcified and non-calcified, were analyzed for MARCH5 expression using western blotting. Mitochondrial fragmentation was evaluated using transmission electron microscope. Osteogenic differentiation of human aortic valvular interstitial cells (HVICs) was induced with osteoblastic medium (OM), confirmed by western blotting and Alizarin red staining. Mitochondrial morphology and oxidative phosphorylation were assessed using MitoTracker and Seahorse, respectively. MARCH5-knockdown and ApoE-knockout mice fed high-fat diet were used to study aortic valve calcification.</div></div><div><h3>Results</h3><div>The mitochondrial quality control was impaired in calcified valves, and the level of MARCH5 protein was also decreased in calcified valves. Inhibition of MARCH5 impaired mitochondrial quality control, increased mitochondrial stress and accelerates osteogenic transformation in OM treated HVICs. While, overexpression MARCH5 has the opposite effects. Co-immunoprecipitation, mass spectrometry and molecular docking found MARCH5 interacted Rac GTPase-activating protein 1 (RACGAP1) and promoted its ubiquitination, leading to impaired mitochondrial quality control. Inhibiting RACGAP1 reversed osteogenic transformation induced by MARCH5 silencing in OM treated HVICs. Silencing dynamin-related protein 1 (DRP1) under RACGAP1 inhibition had no additional benefit. In vivo, deficiency of MARCH5 promoted aortic valve calcification, while inhibition RACGAP1 reversed aortic valve calcification in MARCH5 deficiency mice.</div></div><div><h3>Conclusion</h3><div>Downregulation of MARCH5 promotes RACGAP1 ubiquitination, activating DRP1 and impairing mitochondrial quality control, which contributes to aortic valve calcification. This identifies a potential therapeutic target for aortic valve calcification.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119911"},"PeriodicalIF":4.6,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063510","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}

引用次数: 0

Serum starvation induces cytosolic DNA trafficking via exosome and autophagy-lysosome pathway in microglia

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-01-27 DOI: 10.1016/j.bbamcr.2025.119905

Liyan Zhou, Zilong Wu, Xiaoqing Yi, Dongxue Xie, Jufen Wang, Wenhe Wu

The imbalance of microglial homeostasis is highly associated with age-related neurological diseases, where cytosolic endogenous DNA is also likely to be found. As the main medium for storing biological information, endogenous DNA could be localized to cellular compartments normally free of DNA when cells are stimulated. However, the intracellular trafficking of endogenous DNA remains unidentified. In this study, we demonstrated that nuclear DNA (nDNA) and mitochondrial DNA (mtDNA), as the components of endogenous DNA, undergo different intracellular trafficking under conditions of microglial homeostasis imbalance induced by serum starvation. Upon detecting various components of endogenous DNA in the cytoplasmic and extracellular microglia, we found that cytosolic nDNA primarily exists in a free form and undergoes degradation through the autophagy-lysosome pathway. In contrast, cytosolic mtDNA predominantly exists in a membrane-wrapped form and is trafficked through both exosome and autophagy-lysosome pathways, with the exosome pathway serving as the primary one. When the autophagy-lysosome pathway was inhibited, there was an increase in exosomes. More importantly, the inhibition of the autophagy-lysosome pathway resulted in enhanced trafficking of mtDNA through the exosome pathway. These findings unveiled the crosstalk between these two pathways in the trafficking of microglial cytosolic DNA and thus provide new insights into intervening in age-related neurological diseases.

{"title":"Serum starvation induces cytosolic DNA trafficking via exosome and autophagy-lysosome pathway in microglia","authors":"Liyan Zhou, Zilong Wu, Xiaoqing Yi, Dongxue Xie, Jufen Wang, Wenhe Wu","doi":"10.1016/j.bbamcr.2025.119905","DOIUrl":"10.1016/j.bbamcr.2025.119905","url":null,"abstract":"<div><div>The imbalance of microglial homeostasis is highly associated with age-related neurological diseases, where cytosolic endogenous DNA is also likely to be found. As the main medium for storing biological information, endogenous DNA could be localized to cellular compartments normally free of DNA when cells are stimulated. However, the intracellular trafficking of endogenous DNA remains unidentified. In this study, we demonstrated that nuclear DNA (nDNA) and mitochondrial DNA (mtDNA), as the components of endogenous DNA, undergo different intracellular trafficking under conditions of microglial homeostasis imbalance induced by serum starvation. Upon detecting various components of endogenous DNA in the cytoplasmic and extracellular microglia, we found that cytosolic nDNA primarily exists in a free form and undergoes degradation through the autophagy-lysosome pathway. In contrast, cytosolic mtDNA predominantly exists in a membrane-wrapped form and is trafficked through both exosome and autophagy-lysosome pathways, with the exosome pathway serving as the primary one. When the autophagy-lysosome pathway was inhibited, there was an increase in exosomes. More importantly, the inhibition of the autophagy-lysosome pathway resulted in enhanced trafficking of mtDNA through the exosome pathway. These findings unveiled the crosstalk between these two pathways in the trafficking of microglial cytosolic DNA and thus provide new insights into intervening in age-related neurological diseases.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119905"},"PeriodicalIF":4.6,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063511","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}

引用次数: 0

The key vulnerabilities and therapeutic opportunities in the USP7-p53/MDM2 axis in cancer

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-01-27 DOI: 10.1016/j.bbamcr.2025.119908

Gouranga Saha , Mrinal K. Ghosh

The MDM2/MDMX-p53 circuitry is essential for controlling the development, apoptosis, immune response, angiogenesis, senescence, cell cycle progression, and proliferation of cancer cells. Research has demonstrated that USP7 exerts strong control over p53, MDM2, and MDMX stability, with multiple mediator proteins influencing the USP7-p53-MDM2/MDMX axis to modify p53 expression level and function. In cases where p53 is of the wild type (Wt-p53) in tumors, inhibiting USP7 promotes the degradation of MDM2/MDMX, leading to the activation of p53 signaling. This, in turn, results in cell cycle arrest and apoptosis. Hence, targeting USP7 presents a promising avenue for cancer therapy. Targeting USP7 in tumors that harbor mutant p53 (Mut-p53) is unlikely and remains largely unexplored due to the existence of numerous USP7 targets that function independently of p53. Considering that Mut-p53 exhibits resistance to degradation by MDM2 and other E3 ligases and also shares the same signaling pathways as Wt-p53, it is reasonable to suggest that USP7 may play a role in stabilizing Mut-p53. However, there is still much to be done in this area. If the hypothesis is correct, USP7 may be a potent target in cancers containing both Wt-p53 and Mut-p53.

{"title":"The key vulnerabilities and therapeutic opportunities in the USP7-p53/MDM2 axis in cancer","authors":"Gouranga Saha , Mrinal K. Ghosh","doi":"10.1016/j.bbamcr.2025.119908","DOIUrl":"10.1016/j.bbamcr.2025.119908","url":null,"abstract":"<div><div>The MDM2/MDMX-p53 circuitry is essential for controlling the development, apoptosis, immune response, angiogenesis, senescence, cell cycle progression, and proliferation of cancer cells. Research has demonstrated that USP7 exerts strong control over p53, MDM2, and MDMX stability, with multiple mediator proteins influencing the USP7-p53-MDM2/MDMX axis to modify p53 expression level and function. In cases where p53 is of the wild type (Wt-p53) in tumors, inhibiting USP7 promotes the degradation of MDM2/MDMX, leading to the activation of p53 signaling. This, in turn, results in cell cycle arrest and apoptosis. Hence, targeting USP7 presents a promising avenue for cancer therapy. Targeting USP7 in tumors that harbor mutant p53 (Mut-p53) is unlikely and remains largely unexplored due to the existence of numerous USP7 targets that function independently of p53. Considering that Mut-p53 exhibits resistance to degradation by MDM2 and other E3 ligases and also shares the same signaling pathways as Wt-p53, it is reasonable to suggest that USP7 may play a role in stabilizing Mut-p53. However, there is still much to be done in this area. If the hypothesis is correct, USP7 may be a potent target in cancers containing both Wt-p53 and Mut-p53.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119908"},"PeriodicalIF":4.6,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063513","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}

引用次数: 0

GPSM1 interacts and cooperates with MMP19 to promote proliferation and EMT in colorectal cancer cells

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-01-22 DOI: 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}

引用次数: 0

Mitochondrial quality control: Biochemical mechanism of cardiovascular disease 线粒体质量控制：心血管疾病的生化机制。

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-01-19 DOI: 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.

线粒体在心肌细胞能量稳态和ATP生成的调控中起关键作用。线粒体功能障碍可以引发一些病理事件，有助于心血管疾病的发生和进展。这些机制包括氧化应激的诱导、细胞内钙循环的失调、凋亡途径的激活和脂质代谢的改变。本文综述了线粒体在与心血管疾病相关的细胞内信号传导中的作用，强调了活性氧产生和线粒体动力学的贡献。事实上，线粒体功能障碍涉及心血管疾病的各个方面，目前正被评估为治疗干预的潜在目标。为了治疗心血管疾病和改善整体心脏健康，更好地了解这些生化系统是很重要的。这些发现使得有针对性的治疗和预防措施得以实现。因此，本文综述了不同的研究，这些研究表明线粒体动力学的变化，如融合、裂变和线粒体自噬如何促进心脏病相关疾病的发展或恶化，并总结了它们的作用。

{"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}

引用次数: 0

Interdependent roles for growth differentiation factor-15 (GDF15) and LIMS1 in regulating cell migration: Implications for colorectal cancer metastasis 生长分化因子-15 （GDF15）和LIMS1在调节细胞迁移中的相互作用：对结直肠癌转移的影响

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-01-19 DOI: 10.1016/j.bbamcr.2025.119904

Andria Kotsoni , Louiza Valentina Kozaki , Andreas Stylianou , Vasiliki Gkretsi

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.

结直肠癌（CRC）在全球死亡率中排名第二，而转移占CRC相关死亡的大多数。因此，了解细胞迁移是转移的关键步骤，对于开发新的治疗方法是必不可少的。生长分化因子-15 （GDF15）是转化生长因子β超家族的一员，在结直肠癌中过度表达并促进转移，其机制尚不清楚。LIMS1是一种细胞基质粘附促存活蛋白，在CRC中也过表达，并且定位于肿瘤侵袭前沿，而生物信息学分析表明，这两个基因在转移性CRC样本中表现出相同的表达模式。在本研究中，用人重组GDF15 （hrGDF15）处理低侵袭性HT29 CRC细胞，导致LIMS1表达增加，rhogtpase RAC1和RHOA mRNA水平升高，但CDC42未升高，并且迁移增加。相反，在侵袭性HCT116细胞中，GDF15或LIMS1- sirna介导的沉默分别导致LIMS1和GDF15的下调，RAC1和RHOA的降低以及细胞迁移的减少，这些在GDF15和LIMS1- sirna处理的细胞中通过hrGDF15处理完全恢复。我们的研究结果表明，GDF15和LIMS1在迁移过程中具有相互依赖的作用，这使得它们成为开发抑制转移性扩散的新治疗策略的有效靶点。

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引用次数: 0

(−)-Epigallocatechin-3-gallate promotes the dermal papilla cell proliferation and migration through the induction of VEGFA （-）-表没食子儿茶素-3-没食子酸酯通过诱导VEGFA促进真皮乳头细胞增殖和迁移。

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-01-13 DOI: 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.

真皮乳头细胞（DPCs）对毛囊（HF）的生长发育至关重要。（-）-表没食子儿茶素-3-没食子酸酯（EGCG）是在绿茶中发现的主要儿茶素，具有抗氧化作用和调节细胞活性。本研究表明EGCG能促进DPCs的增殖。此外，EGCG处理显著上调DPCs中PCNA、CCND1、HIF-1α、VEGFA和Bcl-2 mrna的表达，同时显著降低Bax基因的表达。筛选了EGCG的最佳添加浓度。在检测DPCs抗氧化能力时，0.5 μM EGCG处理可增强过氧化氢酶、超氧化物歧化酶和谷胱甘肽的相对活性，促进DPCs的抗氧化能力和迁移能力。随后，通过RNA测序鉴定了DPCs中与EGCG处理相关的差异表达基因（deg），共发现21个差异表达基因，包括VEGFA、POSTN、CLU、SERPINE2和NPY。作为候选基因，我们研究了VEGFA在调控HF生长发育中的作用。免疫荧光染色显示，EGCG处理增强了DPCs中VEGFA和CLU的荧光强度。VEGFA在DPCs中过表达和敲低后，可调节HF的生长和发育相关基因的表达，增强增殖细胞核抗原的表达，促进DPCs增殖。EGCG还可以挽救DPCs中的siRNA-VEGFA效应。本研究提示EGCG可能通过诱导VEGFA表达水平调控DPCs细胞活力，为探讨HF生长机制及毛发相关疾病的治疗提供参考。

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引用次数: 0

Inhibition of methionine aminopeptidase in C2C12 myoblasts disrupts cell integrity via increasing endoplasmic reticulum stress C2C12成肌细胞中蛋氨酸氨基肽酶的抑制通过增加内质网应激破坏细胞完整性。

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-01-13 DOI: 10.1016/j.bbamcr.2025.119901

Shion Osana , Cheng-Ta Tsai , Naoki Suzuki , Kazutaka Murayama , Masaki Kaneko , Katsuhiko Hata , Hiroaki Takada , Yutaka Kano , Ryoichi Nagatomi

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.

蛋白酶体依赖的蛋白质降解和氨基肽酶对肽的消化是肌肉形成所必需的。蛋氨酸氨基肽酶（MetAPs）不仅参与蛋白质的蛋白酶体降解，还参与翻译的调节（通过参与翻译后修饰）。抑制MetAP1和MetAP2表达可抑制C2C12成肌细胞的成肌分化。然而，抑制MetAPs损害细胞功能的分子机制仍有待阐明。在这里，我们为我们的假设提供了证据，即MetAPs调节蛋白质静止，它们的抑制通过破坏翻译后修饰而增加内质网应激，从而损害细胞完整性。因此，我们利用C2C12成肌细胞，研究抑制MetAPs对细胞增殖的影响及其作用的分子机制。我们发现暴露于bengamide B（一种MetAP抑制剂）导致C2C12成肌细胞通过细胞周期阻滞而失去增殖能力。潜在的机制涉及异常蛋白的积累（由于n端蛋氨酸去除功能的减少），导致内质网应激增加，蛋白质合成减少，自噬途径的保护性激活。为了确定参与这些作用的MetAP，我们使用sirna特异性地敲低MetAP1和MetAP2的表达。我们发现只有MetAP2敲除模拟了bengamide B治疗的效果。因此，我们认为MetAP2而不是MetAP1参与维持C2C12成肌细胞的完整性。我们的研究结果有助于理解肌肉再生、肥胖和暴饮暴食失调。它将有助于指导这些疾病的新治疗策略。

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引用次数: 0

Nrf2 mediates mitochondrial and NADPH oxidase-derived ROS during mild heat stress at 40 °C 在40 °C轻度热应激下，Nrf2介导线粒体和NADPH氧化酶衍生的ROS。

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-01-10 DOI: 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.

热疗是化疗和放疗的辅助手段，可使肿瘤对这些治疗变得敏感。然而，反复的热处理导致肿瘤获得耐热性（耐热性）。耐热性是一种适应性生存反应，似乎是由上调的细胞防御介导的。然而，其激活机制尚不清楚。当HeLa细胞在40 °C下轻度热休克3 h时，超氧化物和过氧化物水平升高。用线粒体抗氧化剂MitoQ和NADPH氧化酶（NOX）抑制剂apocynin处理细胞，以表征这两种来源对总活性氧（ROS）池的贡献。我们发现，在40 °C的轻度热休克中，线粒体和NOX都是ROS的来源。热源性活性氧被认为在40 °C时激活适应性生存反应。Nrf2是细胞抗氧化反应的主要调节因子，被认为在建立适应性生存反应中起着关键作用。Nrf2被过度表达或敲低以评估其作用。此外，Nrf2水平与细胞氧化还原状态相关，并通过清除线粒体和nox衍生的ROS来实现。Nrf2的敲除显著增加了被罗布麻素或MitoQ清除的ROS水平。最后，关键的防御蛋白如DJ-1和PGAM5似乎需要一个由Nrf2和线粒体ROS介导的双键激活系统。我们的研究表明，线粒体和nox来源的ROS在激活细胞防御和Nrf2方面是必不可少的，并强调了可能有助于获得耐热性的潜在治疗靶点。

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引用次数: 0