Cell Death & Disease最新文献

{"title":"TIMM23 overexpression drives NSCLC cell growth and survival by enhancing mitochondrial function.","authors":"Jianhua Zha, Jiaxin Li, Hui Yin, Mingjing Shen, Yingchen Xia","doi":"10.1038/s41419-025-07505-3","DOIUrl":"10.1038/s41419-025-07505-3","url":null,"abstract":"<p><p>Mitochondrial hyperfunction is implicated in promoting non-small cell lung cancer (NSCLC) cell growth. TIMM23 (translocase of inner mitochondrial membrane 23) is a core component of the mitochondrial import machinery, facilitating the translocation of proteins across the inner mitochondrial membrane into the matrix. Its expression and potential functions in NSCLC were tested. Comprehensive bioinformatic analysis revealed a strong correlation between TIMM23 overexpression and adverse clinical outcomes in NSCLC patients. Single-cell RNA sequencing data further corroborated these findings, demonstrating elevated TIMM23 expression within the cancer cells of NSCLC mass. Subsequent experimental validation confirmed significantly increased TIMM23 mRNA and protein levels in locally-treated NSCLC tissues compared to matched normal lung tissues. Moreover, TIMM23 expression was consistently elevated across multiple primary/established NSCLC cells. Silencing or ablation of TIMM23 via shRNA or CRISPR/Cas9 in NSCLC cells resulted in impaired mitochondrial function, characterized by reduced complex I activity, ATP depletion, mitochondrial membrane potential dissipation, oxidative stress, and lipid peroxidation. These mitochondrial perturbations coincided with attenuated cell viability, proliferation, and migratory capacity, and concomitant induction of apoptosis. Conversely, ectopic overexpression of TIMM23 significantly enhanced mitochondrial complex I activity and ATP production, promoting NSCLC cell proliferation and motility. In vivo, intratumoral delivery of a TIMM23 shRNA-expressing adeno-associated virus significantly suppressed the growth of subcutaneous NSCLC xenografts in nude mice. Subsequent analysis of tumor tissues revealed depleted TIMM23 expression, ATP reduction, oxidative damage, proliferative arrest, and apoptotic induction. Collectively, these findings establish TIMM23 as a critical pro-tumorigenic factor in NSCLC, highlighting its potential as a prognostic biomarker and therapeutic target.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"174"},"PeriodicalIF":8.1,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11906786/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Both direct and indirect suppression of MCL1 synergizes with BCLXL inhibition in preclinical models of gastric cancer.","authors":"Li-Ping Zhang, Yu-Min Wei, Ming-Jie Luo, Shu-Yue Ren, Xiang-Wen Zhan, Chao Wang, Ze-Feng Li, Rui-Min Zhu, Shuo Yan, Yu Cheng, Jia-Li Xu, Xing-Jiu Yang, Ke-Lei Du, Jin-Qing Wang, Guan-Nan Zhang, De-Xiao Du, Ran Gao, Dong-Bing Zhao, Jia-Nan Gong","doi":"10.1038/s41419-025-07481-8","DOIUrl":"10.1038/s41419-025-07481-8","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Despite the progress of treatment in gastric cancer (GC), the overall outcomes remain poor in patients with advanced diseases, underscoring the urgency to develop more effective treatment strategies. BH3-mimetic drugs, which inhibit the pro-survival BCL2 family proteins, have demonstrated great therapeutic potential in cancer therapy. Although previous studies have implicated a role of targeting the cell survival pathway in GC, the contribution of different pro-survival BCL2 family proteins in promoting survival and mediating resistance to current standard therapies in GC remains unclear. A systematic study to elucidate the hierarchy of these proteins using clinically more relevant GC models is essential to identify the most effective therapeutic target(s) and rational combination strategies for improving GC therapy. Here, we provide evidence from both in vitro and in vivo studies using a broad panel of GC cell lines, tumoroids, and xenograft models to demonstrate that BCLXL and MCL1, but not other pro-survival BCL2 family proteins, are crucial for GC cells survival. While small molecular inhibitors of BCLXL or MCL1 exhibited some single-agent activity, their combination sufficed to cause maximum killing. However, due to the unsolved cardiotoxicity associated with direct MCL1 inhibitors, finding combinations of agents that indirectly target MCL1 and enable the reduction of doses of BCLXL inhibitors while maintaining their anti-neoplastic effects is potentially a feasible approach for the further development of these compounds. Importantly, inhibiting BCLXL synergized significantly with anti-mitotic and HER2-targeting drugs, leading to enhanced anti-tumour activity with tolerable toxicity in preclinical GC models. Mechanistically, anti-mitotic chemotherapies induced MCL1 degradation via the ubiquitin-proteasome pathway mainly through FBXW7, whereas HER2-targeting drugs suppressed MCL1 transcription via the STAT3/SRF axis. Moreover, co-targeting STAT3 and BCLXL also exhibited synergistic killing, extending beyond HER2-amplified GC. Collectively, our results provide mechanistic rationale and pre-clinical evidence for co-targeting BCLXL and MCL1 (both directly and indirectly) in GC. (i) Gastric cancer cells rely on BCLXL and, to a lesser degree, on MCL1 for survival. The dual inhibition of BCLXL and MCL1 with small molecular inhibitors acts synergistically to kill GC cells, regardless of their TCGA molecular subtypes or the presence of poor prognostic markers. While the effect of S63845 is mediated by both BAX and BAK in most cases, BAX, rather than BAK, acts as the primary mediator of BCLXLi in GC cells. (ii) Inhibiting BCLXL significantly synergizes with anti-mitotic and HER2-targeting drugs, leading to enhanced anti-tumour activity with tolerable toxicity in preclinical GC models. Mechanistically, anti-mitotic chemotherapies induce MCL1 degradation via the ubiquitin-proteasome pathway mainly through FBXW7, whereas HER2-targeting drugs suppre","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"170"},"PeriodicalIF":8.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11904182/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143613678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Point mutations of the mitochondrial chaperone TRAP1 affect its functions and pro-neoplastic activity.","authors":"Claudio Laquatra, Alessia Magro, Federica Guarra, Matteo Lambrughi, Lavinia Ferrone, Giulio Fracasso, Melissa Bacchin, Martina La Spina, Elisabetta Moroni, Elena Papaleo, Giorgio Colombo, Andrea Rasola","doi":"10.1038/s41419-025-07467-6","DOIUrl":"10.1038/s41419-025-07467-6","url":null,"abstract":"<p><p>The mitochondrial chaperone TRAP1 is a key regulator of cellular homeostasis and its activity has important implications in neurodegeneration, ischemia and cancer. Recent evidence has indicated that TRAP1 mutations are involved in several disorders, even though the structural basis for the impact of point mutations on TRAP1 functions has never been studied. By exploiting a modular structure-based framework and molecular dynamics simulations, we investigated the effect of five TRAP1 mutations on its structure and stability. Each mutation differentially impacts long-range interactions, intra and inter-protomer dynamics and ATPase activity. Changes in these parameters influence TRAP1 functions, as revealed by their effects on the activity of the TRAP1 interactor succinate dehydrogenase (SDH). In keeping with this, TRAP1 point mutations affect the growth and migration of aggressive sarcoma cells, and alter sensitivity to a selective TRAP1 inhibitor. Our work provides new insights on the structure-activity relationship of TRAP1, identifying crucial amino acid residues that regulate TRAP1 proteostatic functions and pro-neoplastic activity.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"172"},"PeriodicalIF":8.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11903959/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143613681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The effect of TIM1⁺ Breg cells in liver ischemia-reperfusion injury.","authors":"Yu Zhang, Cheng Zhang, Beng Yang, Chuanhui Peng, Jie Zhou, Shenli Ren, Zhenhua Hu","doi":"10.1038/s41419-025-07446-x","DOIUrl":"10.1038/s41419-025-07446-x","url":null,"abstract":"<p><p>Liver transplantation is the only effective method for end-stage liver disease; however, liver ischemia reperfusion injury (IRI) seriously affects donor liver function after liver transplantation. IRI is a pathophysiological process in which organ damage is aggravated after the blood flow and oxygen supply of ischemic organ tissues are restored. It combines the two stages of hypoxic cell stress triggered by ischemia and inflammation-mediated reperfusion injury. Herein, we studied the protective effect and mechanism of the anti-T cell Ig and mucin domain (TIM1) monoclonal antibody, RMT1-10, on hepatic cell injury induced by IRI. First, a liver IRI model was established in vivo. HE, TEM, and Tunel were used to detect liver tissue injury, changes in the liver ultrastructure and liver cell apoptosis, respectively. ELISA were performed to determine the levels of ALT, AST, MDA, GSH, and related inflammatory factors. We found that RMT1-10 could significantly reduce liver injury. Flow cytometry results showed that the number of TIM1⁺ regulatory B cells (Bregs) in the IRI liver increased briefly, while pretreatment with RMT1-10 could increase the number of TIM1⁺ Bregs and interleukin-10 (IL-10) secretion in liver IRI model mice, thus playing a protective role in liver reperfusion. When Anti-CD20 was used to remove B cells, RMT1-10 had a reduced effect on liver IRI. Previous data showed that the number of T helper 1 cells (Th1:CD4⁺; CD8⁺) increased significantly after IRI. RMT1-10 inhibited Th1 cells; however, it significantly activated regulatory T cells. Sequencing analysis showed that RMT1-10 could significantly downregulate the expression of nuclear factor-kappa B (NF-κB) pathway-related genes induced by IRI. These results suggested that RMT1-10 could promote the maturation of B cells through an atypical NF-κB pathway, thereby increasing the number of TIM1⁺ Bregs and associated IL-10 secretion to regulate the inflammatory response, thereby protecting against liver IRI.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"171"},"PeriodicalIF":8.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11903774/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143613683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CHCHD2 rescues the mitochondrial dysfunction in iPSC-derived neurons from patient with Mohr-Tranebjaerg syndrome.","authors":"Yihua Huang, Zirui Chen, Weiling Deng, Yawei Jiang, Yue Pan, Zhirong Yuan, Hailiang Hu, Yongming Wu, Yafang Hu","doi":"10.1038/s41419-025-07472-9","DOIUrl":"10.1038/s41419-025-07472-9","url":null,"abstract":"<p><p>Mohr-Tranebjaerg syndrome (MTS) is a rare X-linked recessive neurodegenerative disorder caused by mutations in the Translocase of Inner Mitochondrial Membrane 8A (TIMM8A) gene, which encodes TIMM8a, a protein localized to the mitochondrial intermembrane space (IMS). The pathophysiology of MTS remains poorly understood. To investigate the molecular mechanisms underlying MTS, we established induced pluripotent stem cells (iPSCs) from a male MTS patient carrying a novel TIMM8A mutation (c.225-229del, p.Q75fs95*), referred to as MTS-iPSCs. To generate an isogenic control, we introduced the same mutation into healthy control iPSCs (CTRL-iPSCs) using the Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated protein 9 (CRISPR/Cas9), resulting in mutant iPSCs (MUT-iPSCs). We differentiated the three iPSC lines into neurons and evaluated their mitochondrial function and neuronal development. Both MTS- and MUT-iPSCs exhibited impaired neuronal differentiation, characterized by smaller somata, fewer branches, and shorter neurites in iPSC-derived neurons. Additionally, these neurons showed increased susceptibility to apoptosis under stress conditions, as indicated by elevated levels of cytochrome c and cleaved caspase-3. Mitochondrial function analysis revealed reduced protein levels and activity of complex IV, diminished ATP synthesis, and increased reactive oxygen species (ROS) generation in MTS- and MUT-neurons. Furthermore, transmission electron microscopy revealed mitochondrial fragmentation in MTS-neurons. RNA sequencing identified differentially expressed genes (DEGs) involved in axonogenesis, synaptic activity, and apoptosis-related pathways. Among these DEGs, coiled-coil-helix-coiled-coil-helix domain-containing 2 (CHCHD2), which encodes a mitochondrial IMS protein essential for mitochondrial homeostasis, was significantly downregulated in MTS-neurons. Western blot analysis confirmed decreased CHCHD2 protein levels in both MTS- and MUT-neurons. Overexpression of CHCHD2 rescued mitochondrial dysfunction and promoted neurite elongation in MTS-neurons, suggesting that CHCHD2 acts as a downstream effector of TIMM8a in the pathogenesis of MTS. In summary, loss-of-function of TIMM8a leads to a downstream reduction in CHCHD2 levels, collectively impairing neurogenesis by disrupting mitochondrial homeostasis. TIMM8a mutation (p.Q75fs95*) leads to mitochondrial dysfunction and neuronal defects in iPSC-derived neurons from patient with Mohr-Tranebjaerg syndrome, which are rescued by overexpression of CHCHD2. TIMM8a translocase of inner mitochondrial membrane 8a, CHCHD2 coiled-coil-helix-coiled-coil-helix domain-containing protein 2, MTS Mohr-Tranebjaerg syndrome, I mitochondrial complex I, II mitochondrial complex II, III mitochondrial complex III, IV mitochondrial complex IV, Q coenzyme Q10, Cyt c cytochrome c.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"173"},"PeriodicalIF":8.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11903874/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143613680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Exosome-mediated delivery of miR-9 induces cancer-associated fibroblast-like properties in human breast fibroblasts.","authors":"Sara Baroni, S Romero-Cordoba, I Plantamura, M Dugo, E D'Ippolito, A Cataldo, G Cosentino, V Angeloni, A Rossini, M G Daidone, M VIorio","doi":"10.1038/s41419-025-07382-w","DOIUrl":"10.1038/s41419-025-07382-w","url":null,"abstract":"","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"169"},"PeriodicalIF":8.1,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11897123/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Maintenance of magnesium homeostasis by NUF2 promotes protein synthesis and anaplastic thyroid cancer progression.","authors":"Lisha Bao, Yingying Gong, Yulu Che, Ying Li, Tong Xu, Jinming Chen, Shanshan Wang, Zhuo Tan, Ping Huang, Zongfu Pan, Minghua Ge","doi":"10.1038/s41419-025-07348-y","DOIUrl":"10.1038/s41419-025-07348-y","url":null,"abstract":"","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"166"},"PeriodicalIF":8.1,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11897368/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Nicotinamide mononucleotide promotes osteogenesis and reduces adipogenesis by regulating mesenchymal stromal cells via the SIRT1 pathway in aged bone marrow.","authors":"Jie Song, Jing Li, Fangji Yang, Gang Ning, Limin Zhen, Lina Wu, Yongyuan Zheng, Qi Zhang, Dongjun Lin, Chan Xie, Liang Peng","doi":"10.1038/s41419-025-07398-2","DOIUrl":"10.1038/s41419-025-07398-2","url":null,"abstract":"","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"168"},"PeriodicalIF":8.1,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11897193/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction Note: Oroxylin A activates PKM1/HNF4 alpha to induce hepatoma differentiation and block cancer progression.","authors":"Libin Wei, Yuanyuan Dai, Yuxin Zhou, Zihao He, Jingyue Yao, Li Zhao, Qinglong Guo, Lin Yang","doi":"10.1038/s41419-025-07496-1","DOIUrl":"10.1038/s41419-025-07496-1","url":null,"abstract":"","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"167"},"PeriodicalIF":8.1,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11897395/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oncogenic and microenvironmental signals drive cell type specific apoptosis resistance in juvenile myelomonocytic leukemia.","authors":"Naile Koleci, Ying Wu, Niels Anton Wehner, Jovana Rajak, Venugopal Rao Mittapalli, Julia Mergner, Hui Xiao, Jun Wang, Madeleine Wahl, Sheila Bohler, Konrad Aumann, Georg Häcker, Senthilkumar Ramamoorthy, Melanie Boerries, Susanne Kirschnek, Miriam Erlacher","doi":"10.1038/s41419-025-07479-2","DOIUrl":"10.1038/s41419-025-07479-2","url":null,"abstract":"<p><p>Juvenile myelomonocytic leukemia (JMML) is caused by constitutively activated RAS signaling and characterized by increased proliferation and predominant myelomonocytic differentiation of hematopoietic cells. Using MxCre;Ptpn11^D61Y/+ mice, which model human JMML, we show that RAS pathway activation affects apoptosis signaling through cell type-dependent regulation of BCL-2 family members. Apoptosis resistance observed in monocytes and granulocytes was mediated by overexpression of the anti-apoptotic and down-regulation of the pro-apoptotic members of the BCL-2 family. Two anti-apoptotic proteins, BCL-X_L and MCL-1, were directly regulated by the oncogenic RAS signaling but, in addition, were influenced by microenvironmental signals. While BCL-X_L and BCL-2 were required for the survival of monocytes, MCL-1 was essential for neutrophils. Interestingly, stem and progenitor cells expressing the oncogenic PTPN11 mutant showed no increased apoptosis resistance. BCL-X_L inhibition was the most effective in killing myeloid cells in vitro but was insufficient to completely resolve myeloproliferation in vivo.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"165"},"PeriodicalIF":8.1,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11890777/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}