[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-detail-345437-en":59,"doc-seo-345437-105":81},{"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":5,"data":60},{"doc_id":61,"user_id":62,"nickname":63,"user_avatar":64,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":66,"doc_content":67,"file_id":68,"file_url":69,"file_type":70,"file_size":71,"view_count":14,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":72,"language":73,"language_code":74,"site_id":75,"html_lang":74,"table_of_contents":76,"faqs":77,"seo_title":78,"seo_description":66,"update_tm":79,"read_time":80},345437,7971461740886,"Theodore","https://ap-avatar.wpscdn.com/davatar_3d24733baf745e90a7e4bdd5f77d97b2","Inhibition of mitochondrial RNA polymerase sensitizes cancer cells to radiation by inhibiting mitochondrial respiration","Radiotherapy is a cornerstone of cancer treatment, but tumor radioresistance and toxicity to normal cells limit its efficacy, motivating radiosensitizers that selectively disrupt cancer-specific pathways. Mitochondria harbor DNA encoding proteins essential for oxidative phosphorylation (OXPHOS). This study evaluates whether IMT1, an inhibitor targeting mitochondrial RNA polymerase (POLRMT), can enhance radiation response. IMT1 increases radiosensitivity by suppressing mitochondrial respiration, promoting radiation-induced apoptosis without altering DNA damage repair or cell-cycle regulation, and galactose rescues the hyper-radiosensitivity. The effect is strongest in OXPHOS-dominant cancer contexts, supporting a mechanism linking impaired mitochondrial respiration to radiosensitization while minimizing harm to normal cells.","Journal of Radiation Research, Vol. 67, No. 3, 2026, pp. 339–356 [https://doi.org/10.1093/jrr/rrag021](https://doi.org/10.1093/jrr/rrag021)  \nAdvance Access Publication: 1 April 2026  \nInhibition of mitochondrial RNA polymerase sensitizes cancer cells to radiation by inhibiting mitochondrial respiration  \nSachiko Tsunoda, Yukina Osawa and Noriko Hosoya*   \nLaboratory of Molecular Radiology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo,  \nBunkyo-ku, Tokyo 113-8655, Japan  \n*Corresponding author. Laboratory of Molecular Radiology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Tel: +81-3-5841-3505; Fax: +81-3-5841-3013; [Email: nhosoya@m.u-tokyo.ac.jp](Email: nhosoya@m.u-tokyo.ac.jp)  \n(Received 23 July 2025; revised 23 February 2026; accepted 9 March 2026)  \nABSTRACT  \nRadiotherapy is a cornerstone of cancer treatment, but its efficacy is limited by tumor radioresistance and toxicity to normal cells. Thus, radiosensitizing agents that selectively target cancer-specific pathways are needed. Mitochondria contain their own deoxyribonucleic acid (DNA) that encodes proteins essential for oxidative phosphorylation (OXPHOS), the primary energy source for cell growth and survival. Recently, IMT1, a specific inhibitor of mitochondrial transcription targeting mitochondrial RNA polymerase (POLRMT), was developed and shown to suppress tumor growth in several cancers overexpressing POLRMT. However, the effect of combining IMT1 with radiation remains uncharacterized. Here, we show that IMT1 enhances radiosensitivity in cancer cells by inhibiting mitochondrial respiration. We inhibited POLRMTby administrating sublethal dose of IMT1 in OXPHOSdependent cancer cell lines HeLa, A549, MDA-MB-468, HCT116, A431 and AN3CA, and observed increased radiosensitivity. While radiation alone upregulated mitochondrial respiration, IMT1 abolished this capacity when combined with radiation, showing very low oxygen consumption rates in all respiratory states. IMT1 enhanced radiation-induced apoptosis, but did not affect DNA damage repair and cell cycle regulation. Supplementation with galactose rescued hyper-radiosensitivity induced by IMT1. These findings support the mechanistic link between impaired mitochondrial respiration and radiosensitization induced by POLRMT inhibition. The radiosensitizing effect of IMT1 was not observed in normal cell lines RPE1 and HME1 and the glycolysis-dominant cancer cell line HT1080, suggesting that OXPHOS-dominant cancers would profit most from POLRMT inhibition. Thus, this study presents a novel therapeutic strategy that may improve the efficacy of radiotherapy in OXPHOS-dependent cancer cells while minimizing damage to normal cells.  \nKeywords: IMT1; mitochondrial transcription; mitochondrial RNA polymerase; mitochondrial respiration;  \nradiosensitization  \nINTRODUCTION  \nRadiotherapy is widely used to treat cancers and exerts its antitumor effects by inducing deoxyribonucleic acid (DNA) damage. While technological, physical and biological advances have improved the efficacy of radiotherapy, radioresistance in cancer cells and toxicity to normal cells remain significant challenges. A promising approach to overcome these obstacles is the development of molecularly targeted radiosensitizing agents that selectively sensitize cancer cells to ionizing radiation without damaging normal tissues. Since such agents should exhibit selective activity in cancer cells, it is important to identify candidate  \ntargets that are preferentially active in cancer cells but not in normal cells.  \nEnergy-producing metabolic pathways are crucial for cell survival and growth. Mitochondria are vital for cellular energy metabolism and respiration. They produce cellular energy in the form of adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS)  \n[ 1]. The","cbCaig1FgopdZqRu","https://ap.wps.com/l/cbCaig1FgopdZqRu","pdf",2548738,18,"English","en",105,"# Abstract\n# Introduction","[{\"question\":\"What is IMT1 and what target does it inhibit?\",\"answer\":\"IMT1 is a specific inhibitor of mitochondrial transcription that targets mitochondrial RNA polymerase (POLRMT).\"},{\"question\":\"How does IMT1 affect cancer cells when combined with radiation?\",\"answer\":\"IMT1 enhances radiosensitivity by inhibiting mitochondrial respiration, increases radiation-induced apoptosis, and shows very low oxygen consumption rates across respiratory states when combined with radiation.\"},{\"question\":\"Does IMT1 change DNA damage repair or cell cycle regulation?\",\"answer\":\"IMT1 enhances radiation-induced apoptosis, but it does not affect DNA damage repair and cell cycle regulation.\"}]","Inhibition of mitochondrial RNA polymerase sensitizes cancer cells to radiation by inhibiting mitochondrial respiration | PDF",1790057680,45,{"code":4,"msg":82,"data":83},"ok",{"site_id":75,"language":74,"slug":84,"title":65,"keywords":85,"description":66,"schema_data":86,"social_meta":140,"head_meta":142,"extra_data":144,"updated_unix":145},"inhibition-of-mitochondrial-rna-polymerase-sensitizes-cancer-cells-to-radiation-by-inhibiting-mitochondrial-respiration","",{"@graph":87,"@context":139},[88,102,122],{"@type":89,"itemListElement":90},"BreadcrumbList",[91,95,97,100],{"item":92,"name":93,"@type":94,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":96,"name":9,"@type":94,"position":14},"https://docshare.wps.com/document/",{"item":98,"name":40,"@type":94,"position":99},"https://docshare.wps.com/document/research-report/",3,{"item":101,"name":65,"@type":94,"position":19},"https://docshare.wps.com/document/inhibition-of-mitochondrial-rna-polymerase-sensitizes-cancer-cells-to-radiation-by-inhibiting-mitochondrial-respiration/345437/",{"url":101,"name":65,"@type":103,"image":104,"author":109,"headline":65,"publisher":111,"fileFormat":114,"inLanguage":74,"description":66,"dateModified":115,"datePublished":116,"encodingFormat":114,"isAccessibleForFree":117,"interactionStatistic":118},"DigitalDocument",{"url":105,"@type":106,"width":107,"height":108},"https://docshare.wps.com/thumbnails/inhibition-of-mitochondrial-rna-polymerase-sensitizes-cancer-cells-to-radiation-by-inhibiting-mitochondrial-respiration/345437.png","ImageObject",300,407,{"name":63,"@type":110},"Person",{"url":92,"name":112,"@type":113},"DocShare","Organization","application/pdf","2026-09-23","2026-09-22",true,{"@type":119,"interactionType":120,"userInteractionCount":14},"InteractionCounter",{"@type":121},"ViewAction",{"@type":123,"mainEntity":124},"FAQPage",[125,131,135],{"name":126,"@type":127,"acceptedAnswer":128},"What is IMT1 and what target does it inhibit?","Question",{"text":129,"@type":130},"IMT1 is a specific inhibitor of mitochondrial transcription that targets mitochondrial RNA polymerase (POLRMT).","Answer",{"name":132,"@type":127,"acceptedAnswer":133},"How does IMT1 affect cancer cells when combined with radiation?",{"text":134,"@type":130},"IMT1 enhances radiosensitivity by inhibiting mitochondrial respiration, increases radiation-induced apoptosis, and shows very low oxygen consumption rates across respiratory states when combined with radiation.",{"name":136,"@type":127,"acceptedAnswer":137},"Does IMT1 change DNA damage repair or cell cycle regulation?",{"text":138,"@type":130},"IMT1 enhances radiation-induced apoptosis, but it does not affect DNA damage repair and cell cycle regulation.","https://schema.org",{"og:url":101,"og:type":141,"og:title":65,"og:site_name":112,"og:description":66},"article",{"robots":143,"canonical":101},"index,follow",{"doc_id":61,"site_id":75},1790174208]