{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T19:36:04Z","timestamp":1785526564577,"version":"3.56.0"},"posted":{"date-parts":[[2026,7,28]]},"group-title":"Cancer Biology","reference-count":34,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T00:00:00Z","timestamp":1785196800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["R03 CA280489"],"award-info":[{"award-number":["R03 CA280489"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["K22 CA282363"],"award-info":[{"award-number":["K22 CA282363"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01 CA255344"],"award-info":[{"award-number":["R01 CA255344"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01 CA262388"],"award-info":[{"award-number":["R01 CA262388"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,28]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>Decades of research have shown that tumor hypoxia is associated with resistance to anti-cancer treatments. Analysis of TCGA gene expression profiles indicates that NSCLC is among the most hypoxic of cancers despite the high levels of oxygen in the surrounding lung tissue. Several groups have shown that extrinsic factors such as poorly formed tumor vascular contributes to tumor hypoxia. Here, we have investigated the possibility that genetic abnormalities within the tumor also contribute to the development of hypoxia. Our analysis of NSCLC patient datasets in the Cancer Genome Atlas (TCGA) PanCancer and ORIEN datasets revealed a strong correlation between tumor hypoxia and amplification of chromosome 3q which is found in up to 40% of NSCLC. Several oncogenic driver genes have been identified in 3q, and we identified a passenger gene encoding mitochondrial complex I subunit NDUFB5 at 3q26.33. To provide experimental evidence that NDUFB5 amplification can drive tumor hypoxia, we have used CRISPR activation technology to generate murine cells overexpressing the endogenous NDUFB5 gene. We found that cells overexpressing NDUFB5 have elevated rates of oxygen consumption, and tumors grown from these cells have increased amounts of hypoxia with associated treatment resistance. Here, we investigate the impact of manipulating NDUFB5 gene expression on mitochondrial complex I activity and experimentally validate the clinical observations that NDUFB5 overexpression leads to increased levels of intratumoral hypoxia and increased resistance to radiation therapy and immunotherapy.<\/jats:p>","DOI":"10.64898\/2026.07.27.741033","type":"posted-content","created":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T14:45:19Z","timestamp":1785249919000},"source":"Crossref","is-referenced-by-count":0,"title":["Mitochondrial Oxygen Consumption Drives Lung Tumor Hypoxia and Resistance to Therapy via Copy Number Alteration in Mitochondrial Electron Transport Subunit NDUFB5"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3116-445X","authenticated-orcid":false,"given":"Martin","family":"Benej","sequence":"first","affiliation":[{"name":"Ohio State University College of Medicine Department of Molecular Medicine and Therapeutics, OSU Comprehensive Cancer 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43210"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Dravillas","sequence":"additional","affiliation":[{"name":"Ohio State University Wexner School of Medicine Department of Internal Medicine, OSU Comprehensive Cancer Center, and Pelotonia Institute for Immuno-Oncology, Columbus OH 43210"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Hoyd","sequence":"additional","affiliation":[{"name":"Ohio State University Wexner School of Medicine Department of Internal Medicine, OSU Comprehensive Cancer Center, and Pelotonia Institute for Immuno-Oncology, Columbus OH 43210"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esin Bayrali-","family":"Ulker","sequence":"additional","affiliation":[{"name":"Ohio State University Wexner School of Medicine Department of Radiation Oncology, OSU Comprehensive Cancer Center, and Pelotonia Institute for Immuno-Oncology, Columbus OH 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