Cell Death & Disease最新文献

{"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}

{"title":"Novel function of TREK-1 in regulating adipocyte differentiation and lipid accumulation.","authors":"Ajung Kim, Seoyeong Jung, Yongeun Kim, Jonghoon Jung, Soomin Lee, Hojin Lee, Min Jung Kim, Jae-Yong Park, Eun Mi Hwang, Jaekwang Lee","doi":"10.1038/s41419-025-07478-3","DOIUrl":"10.1038/s41419-025-07478-3","url":null,"abstract":"<p><p>K2P (two-pore domain potassium) channels, a diversified class of K⁺-selective ion channels, have been found to affect a wide range of physiological processes in the body. Despite their established significance in regulating proliferation and differentiation in multiple cell types, K2P channels' specific role in adipogenic differentiation (adipogenesis) remains poorly understood. In this study, we investigated the engagement of K2P channels, specifically KCNK2 (also known as TREK-1), in adipogenesis using primary cultured adipocytes and TREK-1 knockout (KO) mice. Our findings showed that TREK-1 expression in adipocytes decreases substantially during adipogenesis. This typically causes an increased Ca²⁺ influx and alters the electrical potential of the cell membrane in 3T3-L1 cell lines. Furthermore, we observed an increase in differentiation and lipid accumulation in both 3T3-L1 cell lines and primary cultured adipocytes when the TREK-1 activity was blocked with Spadin, the specific inhibitors, and TREK-1 shRNA. Finally, our findings revealed that mice lacking TREK-1 gained more fat mass and had worse glucose tolerance when fed a high-fat diet (HFD) compared to the wild-type controls. The findings demonstrate that increase of the membrane potential at adipocytes through the downregulation of TREK-1 can influence the progression of adipogenesis.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"164"},"PeriodicalIF":8.1,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11890776/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584817","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":"Menin maintains lysosomal and mitochondrial homeostasis through epigenetic mechanisms in lung cancer.","authors":"Jun-Bo Yuan, Gui-Xin Gu, Bang-Ming Jin, Qing Han, Bing-Hui Li, Li Zhang, Bin Xu, Xuan Zhu, Guang-Hui Jin","doi":"10.1038/s41419-025-07489-0","DOIUrl":"10.1038/s41419-025-07489-0","url":null,"abstract":"<p><p>Lysosome-mediated autophagy (including mitophagy) is crucial for cell survival and homeostasis. Although the mechanisms of lysosome activation during stress are well recognized, the epigenetic regulation of lysosomal gene expression remains largely unexplored. Menin, encoded by the MEN1 gene, is a chromatin-related protein that is widely involved in gene transcription via histone modifications. Here, we report that menin regulates the transcription of specific lysosomal genes, such as CTSB, CTSE, and TFE3, through MLL-mediated H3K4me3 reprogramming, which is necessary for maintaining lysosomal homeostasis. Menin also directly controls the expression of SQSTM1 and MAP1LC3B to maintain autophagic flux in a manner independent of AMPK/mTORC1 pathways. Furthermore, loss of menin led to mitochondrial dysfunction, elevated levels of reactive oxygen species (ROS), and genome instability. In genetically engineered mouse models, Men1 deficiency resulted in severe lysosomal and mitochondrial dysfunction and an impaired self-clearance ability, which further led to metabolite accumulation. SP2509, a histone demethylase inhibitor, effectively reversed the downregulation of lysosomal and mitochondrial genes caused by loss of Men1. Our study confirms the previously unrecognized biological and mechanistic importance of menin-mediated H3K4me3 in maintaining organelle homeostasis.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"163"},"PeriodicalIF":8.1,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11890858/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584786","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: The miR-30a-5p/CLCF1 axis regulates sorafenib resistance and aerobic glycolysis in hepatocellular carcinoma.","authors":"Zhongqiang Zhang, Xiao Tan, Jing Luo, Hongliang Yao, Zhongzhou Si, Jing-Shan Tong","doi":"10.1038/s41419-025-07492-5","DOIUrl":"10.1038/s41419-025-07492-5","url":null,"abstract":"","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"162"},"PeriodicalIF":8.1,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11889077/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584819","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":"SLC5A3 depletion promotes apoptosis by inducing mitochondrial dysfunction and mitophagy in gemcitabine-resistant pancreatic cancer cells.","authors":"Minsoo Kim, Woosol Chris Hong, Hyeon Woong Kang, Ju Hyun Kim, Dongyong Lee, Jae-Ho Cheong, Hye-Sol Jung, Wooil Kwon, Jin-Young Jang, Hyo Jung Kim, Joon Seong Park","doi":"10.1038/s41419-025-07476-5","DOIUrl":"10.1038/s41419-025-07476-5","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with poor prognosis, largely due to the rapid development of chemoresistance in patients. Mitochondrial dynamics play a crucial role in cancer cell survival. Currently, the specific mechanisms underlying gemcitabine resistance in PDAC remain unknown. In this study, we identified the sodium/myo-inositol co-transporter solute carrier family 5 member 3 (SLC5A3) as a key modulator promoting chemoresistance in PDAC. SLC5A3 levels were significantly upregulated in gemcitabine-resistant PDAC cells, enhancing their cell survival by stabilizing the mitochondrial functions and inhibiting apoptosis. Mitochondrial analysis showed that SLC5A3 inhibition disrupted the mitochondrial dynamics, leading to increased reactive oxygen species production, mitochondrial fission, and impaired oxidative phosphorylation. Moreover, SLC5A3 inhibition activated the PTEN-induced kinase 1/Parkin-mediated mitophagy pathway, resulting in the excessive removal of damaged and healthy mitochondria, thereby depleting the mitochondrial reserves and sensitizing the cells to apoptosis. In vivo studies revealed that targeting SLC5A3 enhanced the efficacy of gemcitabine and significantly reduced the tumor growth. Collectively, these results suggest SLC5A3-mediated mitochondrial regulation as a promising therapeutic strategy to overcome gemcitabine resistance in PDAC.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"161"},"PeriodicalIF":8.1,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11889219/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584820","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}