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Although cyclin D1 increases, combined MTLN silencing with BSO and auranofin yields partial resistance to ROS toxicity, supporting an MTLN-driven H2O2 signaling role in G1/S transition and NSCLC growth.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/healthcare/","Healthcare",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/mitoregulin-promotes-cell-cycle-progression-in-non-small-cell-lung-cancer-cells/367236/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/mitoregulin-promotes-cell-cycle-progression-in-non-small-cell-lung-cancer-cells/367236.png","ImageObject",300,407,{"name":42,"@type":43},"Miles","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-10-29","2026-09-23",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",11,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"What is mitoregulin (MTLN) and why is it relevant to NSCLC?","Question",{"text":63,"@type":64},"MTLN is a 56-amino-acid mitochondrial microprotein that modulates mitochondrial energetics. MTLN gene expression is elevated across many cancers, and its expression patterns have been proposed as prognostic indicators in NSCLC.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"How does silencing MTLN affect NSCLC cell growth and cell-cycle distribution?",{"text":68,"@type":64},"MTLN silencing slows proliferation and increases the proportion of cells in the G1 phase. It also shows protein changes consistent with G1 arrest, including reduced ERK/MYC/CDK2/RB signals and elevated p27Kip1.",{"name":70,"@type":61,"acceptedAnswer":71},"How does MTLN silencing influence oxidative stress signaling and response to ROS-inducing drugs?",{"text":72,"@type":64},"MTLN silencing lowers steady-state cytosolic and mitochondrial H2O2 levels, as measured by a roGFP2-Orp1 redox sensor. Clonogenic survival after BSO and auranofin treatment is greater in MTLN-silenced cultures than controls, suggesting reduced vulnerability to ROS damage linked to G1 status.","https://schema.org",{"og:url":32,"og:type":75,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":77,"canonical":32},"index,follow",{"doc_id":79,"site_id":7},367236,1790503631,{"code":4,"msg":82,"data":83},"success",[84,88,92,96,101,106,110,115,120,123,127],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":85,"show_sort_weight":86,"slug":87},"Story & Novel",90,"story-novel",{"id":26,"doc_module":4,"doc_module_name":25,"category_name":89,"show_sort_weight":90,"slug":91},"Literature",80,"literature",{"id":33,"doc_module":4,"doc_module_name":25,"category_name":93,"show_sort_weight":94,"slug":95},"Exam",70,"exam",{"id":97,"doc_module":4,"doc_module_name":25,"category_name":98,"show_sort_weight":99,"slug":100},5,"Comic",60,"comic",{"id":102,"doc_module":4,"doc_module_name":25,"category_name":103,"show_sort_weight":104,"slug":105},6,"Technology",50,"technology",{"id":107,"doc_module":4,"doc_module_name":25,"category_name":29,"show_sort_weight":108,"slug":109},7,40,"healthcare",{"id":111,"doc_module":4,"doc_module_name":25,"category_name":112,"show_sort_weight":113,"slug":114},8,"Research & Report",30,"research-report",{"id":116,"doc_module":4,"doc_module_name":25,"category_name":117,"show_sort_weight":118,"slug":119},9,"Religion & Spirituality",20,"religion-spirituality",{"id":118,"doc_module":4,"doc_module_name":25,"category_name":121,"show_sort_weight":118,"slug":122},"World Cup","world-cup",{"id":124,"doc_module":4,"doc_module_name":25,"category_name":125,"show_sort_weight":124,"slug":126},10,"Lifestyle","lifestyle",{"id":128,"doc_module":4,"doc_module_name":25,"category_name":129,"show_sort_weight":97,"slug":130},19,"General","general",{"code":4,"msg":82,"data":132},{"doc_id":79,"user_id":133,"nickname":42,"user_avatar":134,"doc_module":4,"category_id":107,"category_name":29,"doc_title":10,"doc_description":12,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":55,"is_deleted":4,"is_public":22,"is_downloadable":22,"audit_status":22,"page_count":140,"language":141,"language_code":8,"site_id":7,"html_lang":8,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":12,"update_tm":145,"read_time":146},13056703019404,"https://ap-avatar.wpscdn.com/davatar_29158cc5080c5b710cf443261637dec0","Article  \nMitoregulin Promotes Cell Cycle Progression in Non-Small Cell Lung Cancer Cells  \nColleen S. Stein 1, *,†, Connor R. Linzer 1,†, Collin D. Heer 2, Nathan H. Witmer 1, Jesse D. Cochran 1, Douglas R. Spitz 2 and Ryan L. Boudreau 1, *  \nAcademic Editor: Richard Seonghun Nho  \nReceived: 23 December 2024  \nRevised: 18 February 2025  \nAccepted: 20 February 2025  \nPublished: 24 February 2025  \nCitation: Stein, C.S.; Linzer, C.R.; Heer, C.D.; Witmer, N.H.; Cochran, J.D.; Spitz, D.R.; Boudreau, R.L. Mitoregulin Promotes Cell Cycle Progression in Non-Small Cell Lung Cancer Cells. Int. J. Mol. Sci. 2025, 26, 1939. [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)ijms26051939  \nCopyright: © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://creativecommons.org/](https://creativecommons.org/)[ ](https://creativecommons.org/)[licenses/by/4.0/](licenses/by/4.0/)) .  \n1 Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA;  \n[Clinzer@mcw.edu](Clinzer@mcw.edu) (C.R.L.); [nathan-witmer@uiowa.edu](nathan-witmer@uiowa.edu) (N.H.W.); [jc6gdt@virginia.edu](jc6gdt@virginia.edu) (J.D.C.)  \n2 Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA; [collin.heer@yale.edu](collin.heer@yale.edu) (C.D.H.); [douglas-spitz@uiowa.edu](douglas-spitz@uiowa.edu) (D.R.S.)  \n* Correspondence: [colleen-stein@uiowa.edu](colleen-stein@uiowa.edu) (C.S.S.); [ryan-boudreau@uiowa.edu](ryan-boudreau@uiowa.edu) (R.L.B.)† These authors contributed equally to this work.  \nAbstract: Mitoregulin (MTLN) is a 56-amino-acid mitochondrial microprotein known to modulate mitochondrial energetics. MTLN gene expression is elevated broadly across most cancers and has been proposed as a prognostic biomarker for non-small cell lung cancer (NSCLC). In addition, lower MTLN expression in lung adenocarcinoma (LUAD) correlates with significantly improved patient survival. In our studies, we have found that MTLN silencing in A549 NSCLC cells slowed proliferation and, in accordance with this, we observed the following: (1) increased proportion of cells in the G1 phase of cell cycle; (2) protein changes consistent with G1 arrest (e.g., reduced levels and/or reduced phosphorylation of ERK, MYC, CDK2, and RB, and elevated p27Kip1 ); (3) reduction inclonogenic cell survival and; (4) lower steady-state cytosolic and mitochondrial H 2O2 levels as indicated by use of the roGFP2-Orp1 redox sensor. Conflicting with G1 arrest, we observed a boost in cyclin D1 abundance. We also tested MTLN silencing in combination with buthionine sulfoximine (BSO) and auranofin (AF), drugs that inhibit GSH synthesis and thioredoxin reductase, respectively, to elevate the reactive oxygen species (ROS) amount to a toxic range. Interestingly, clonogenic survival after drug treatment was greater for MTLN-silenced cultures versus the control cultures. Lower H2O2 output and reduced vulnerability to ROS damage due to G1 status may have jointly contributed to the partial BSO + AF resistance. Overall, our results provide evidence that MTLN fosters H 2O2 signaling to propel G1/S transition and suggest MTLN silencing as a therapeutic strategy to limit NSCLC growth.  \nKeywords: mitochondria; long non-coding RNA; oxidative stress; micropeptide; oxidant; prooxidant; miR-17; cancer therapy; cell cycle arrest; LINC00116  \n1. Introduction  \nCancer continues to be the second leading cause of death within the US, with estimations of ~2 million new cases and ~600,000 cancer-related deaths in 2024 [1] . Lung and bronchus cancer account for the largest percentage of cancer-related deaths, at roughly 21%[1] . Non-small cell lung cancer (NSCLC) is the primary type of lung cancer at 80%, with lung adenoc","cbCairljQCvVrrm2","https://ap.wps.com/l/cbCairljQCvVrrm2","pdf",3642547,22,"English","# Abstract\n# Introduction\n## Microproteins and cancer research\n## LINC00116 and mitoregulin (MTLN) background","[{\"question\":\"What is mitoregulin (MTLN) and why is it relevant to NSCLC?\",\"answer\":\"MTLN is a 56-amino-acid mitochondrial microprotein that modulates mitochondrial energetics. MTLN gene expression is elevated across many cancers, and its expression patterns have been proposed as prognostic indicators in NSCLC.\"},{\"question\":\"How does silencing MTLN affect NSCLC cell growth and cell-cycle distribution?\",\"answer\":\"MTLN silencing slows proliferation and increases the proportion of cells in the G1 phase. It also shows protein changes consistent with G1 arrest, including reduced ERK/MYC/CDK2/RB signals and elevated p27Kip1.\"},{\"question\":\"How does MTLN silencing influence oxidative stress signaling and response to ROS-inducing drugs?\",\"answer\":\"MTLN silencing lowers steady-state cytosolic and mitochondrial H2O2 levels, as measured by a roGFP2-Orp1 redox sensor. Clonogenic survival after BSO and auranofin treatment is greater in MTLN-silenced cultures than controls, suggesting reduced vulnerability to ROS damage linked to G1 status.\"}]","Mitoregulin Promotes Cell Cycle Progression in Non-Small Cell Lung Cancer Cells | PDF",1790169842,55]