[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-342602-105":59,"doc-detail-342602-en":131},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":124,"head_meta":126,"extra_data":128,"updated_unix":130},105,"en","a-first-in-class-timm44-blocker-inhibits-bladder-cancer-cell-growth-article","A first-in-class TIMM44 blocker inhibits bladder cancer cell growth - Article","","TIMM44 expression is significantly elevated in human bladder cancer tissues and cells, and the first-in-class TIMM44 inhibitor MB-10 (MitoBloCK-10) shows strong anti-cancer effects. MB-10 decreases cell viability, proliferation and motility, triggers apoptosis and cell cycle arrest, and disrupts mitochondrial functions by causing depolarization, oxidative stress and ATP reduction. Cytotoxicity is rescued by exogenous ATP or N-acetylcysteine. TIMM44 depletion via CRISPR-Cas9 reproduces inhibition, whereas TIMM44 overexpression enhances growth. In vivo, intraperitoneal MB-10 and TIMM44 depletion suppress bladder cancer xenograft growth in nude mice with corresponding oxidative stress, ATP reduction and Akt-S6K1 inhibition.",{"@graph":69,"@context":123},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/a-first-in-class-timm44-blocker-inhibits-bladder-cancer-cell-growth-article/342602/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/a-first-in-class-timm44-blocker-inhibits-bladder-cancer-cell-growth-article/342602.png","ImageObject",300,407,{"name":92,"@type":93},"Finn","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-29","2026-09-22",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",12,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What evidence shows TIMM44 is relevant to bladder cancer?","Question",{"text":113,"@type":114},"TIMM44 mRNA and protein levels are significantly elevated in human bladder cancer tissues and cells. TIMM44 depletion also produces robust anti-bladder cancer activity, supporting its functional role.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"How does MB-10 inhibit bladder cancer cells?",{"text":118,"@type":114},"MB-10 suppresses cell viability, proliferation and motility, induces apoptosis and cell cycle arrest, and disrupts mitochondrial functions, including depolarization, oxidative stress and ATP reduction.",{"name":120,"@type":111,"acceptedAnswer":121},"Why do ATP supplementation and N-acetylcysteine affect MB-10 cytotoxicity?",{"text":122,"@type":114},"Exogenous ATP and the antioxidant N-acetylcysteine mitigate MB-10-induced cytotoxicity, indicating that mitochondrial ATP reduction and oxidative stress are key contributors to MB-10 effects.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},342602,1790894537,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":140,"language":141,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":67,"update_tm":145,"read_time":146},34359740700684,"https://ap-avatar.wpscdn.com/avatar/1f400023980c374ae676?_k=1777273430885731487","[www.nature.com/cddis](www.nature.com/cddis)  \nARTICLE OPEN   \nA first-in-class TIMM44 blocker inhibits bladder cancer cell growth  \nLifeng Zhang 1,2,5, Xiaokai Shi1,5, Lei Zhang 1,5, Yuanyuan Mi 3, Li Zuo 1 ✉ and Shenglin Gao 1,2,4 ✉  \n© The Author(s) 2024  \n|  |  |  |\n| --- | --- | --- |\n|  | Mitochondria play a multifaceted role in supporting bladder cancer progression. Translocase of inner mitochondrial membrane 44 (TIMM44) is essential for maintaining function and integrity of mitochondria. We here tested the potential effect of MB-10 (MitoBloCK-10), a first-in-class TIMM44 blocker, against bladder cancer cells. TIMM44 mRNA and protein expression is significantly elevated in both human bladder cancer tissues and cells. In both patient-derived primary bladder cancer cells and immortalized (T24) cell line, MB-10 exerted potent anti-cancer activity and inhibited cell viability, proliferation and motility. The TIMM44 blocker induced apoptosis and cell cycle arrest in bladder cancer cells, but failed to provoke cytotoxicity in primary bladder epithelial cells. MB-10 disrupted mitochondrial functions in bladder cancer cells, causing mitochondrial depolarization, oxidative stress and ATP reduction. Whereas exogenously-added ATP and the antioxidant N-Acetyl Cysteine mitigated MB-10-induced cytotoxicity of bladder cancer cells. Genetic depletion of TIMM44 through CRISPR-Cas9 method also induced robust anti-bladder cancer cell activity and MB-10 had no effect in TIMM44-depleted cancer cells. Contrarily, ectopic overexpression of TIMM44 using a lentiviral construct augmented proliferation and motility of primary bladder cancer cells. TIMM44 is important for Akt-mammalian target of rapamycin (mTOR) activation. In primary bladder cancer cells, Akt-S6K1 phosphorylation was decreased by MB-10 treatment or TIMM44 depletion, but enhanced after ectopic TIMM44 overexpression. In vivo, intraperitoneal injection of MB-10 impeded bladder cancer xenograft growth in nude mice. Oxidative stress, ATP reduction, Akt-S6K1 inhibition and apoptosis were detected in MB-10-treated xenograft tissues. Moreover, genetic depletion of TIMM44 also arrested bladder cancer xenograft growth in nude mice, leading to oxidative stress, ATP reduction and Akt-S6K1 inhibition in xenograft tissues. Together, targeting overexpressed TIMM44 |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n| by MB-10 significantly inhibits bladder cancer cell growth in vitro and in vivo. |  |  |\n|  | Cell Death and Disease (2024)15:204; [https://doi.org/10.1038/s41419-024-06585-x](https://doi.org/10.1038/s41419-024-06585-x) |  |\n|  |  |  |\n\nINTRODUCTION  \nBladder cancer is still one of the most common tumor in the population [1, 2] and the long-term survival rate of patients with advanced disease (i.e., metastatic cancer) is still very low [3, 4] . The main treatment for non-muscle-invasive bladder cancer is complete tumor resection combined with intravesical vaccines, chemotherapy and maintenance immunotherapy [5–7] . Treatment options for muscle-invasive bladder cancer mainly include radical cystectomy and neoadjuvant chemotherapy, along with other treatments [5–7], with immunotherapy emerging as a viable treatment for patients who fail first-line chemotherapy [5–7] . Bladder cancer is genetically heterogeneous and surrounded by a complex tissue microenvironment [6, 8–10] . Understanding the molecular biology of bladder cancer will help develop new molecularly-targeted therapies [6, 8–10] .  \nDysregulation of mitochondrial functions can impact bladder cancer progression through several mechanisms. Mitochondria play a multifaceted role in supporting the survival, proliferation  \nand metastatic potential of bladder cancer cells, making thema crucial target for potential therapeutic interventions [9, 11–14] . Altered mitochondrial energy metabolism, apoptotic resis","cbCaipIhVX3ETGcS","https://ap.wps.com/l/cbCaipIhVX3ETGcS","pdf",7442695,14,"English","# Introduction\n## Background on bladder cancer and treatment\n## Mitochondrial dysfunction in bladder cancer\n## Role of TIMM44 and mitochondrial import","[{\"question\":\"What evidence shows TIMM44 is relevant to bladder cancer?\",\"answer\":\"TIMM44 mRNA and protein levels are significantly elevated in human bladder cancer tissues and cells. TIMM44 depletion also produces robust anti-bladder cancer activity, supporting its functional role.\"},{\"question\":\"How does MB-10 inhibit bladder cancer cells?\",\"answer\":\"MB-10 suppresses cell viability, proliferation and motility, induces apoptosis and cell cycle arrest, and disrupts mitochondrial functions, including depolarization, oxidative stress and ATP reduction.\"},{\"question\":\"Why do ATP supplementation and N-acetylcysteine affect MB-10 cytotoxicity?\",\"answer\":\"Exogenous ATP and the antioxidant N-acetylcysteine mitigate MB-10-induced cytotoxicity, indicating that mitochondrial ATP reduction and oxidative stress are key contributors to MB-10 effects.\"}]","A first-in-class TIMM44 blocker inhibits bladder cancer cell growth - Article | PDF",1790047345,35]