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As ROS generation is a byproduct of this metabolism, reducing power in the form of nicotinamide adenine dinucleotide phosphate (NADPH) is required to mitigate oxidative stress in response to this heightened mitochondrial activity. Nicotinamide nucleotide transhydrogenase (NNT) is known to sustain mitochondrial antioxidant capacity through the generation of NADPH; however, its function in non-small cell lung cancer (NSCLC) has not been established. We found that NNT expression significantly enhances tumor formation and aggressiveness in mouse models of lung tumor initiation and progression. We further show that NNT loss elicits mitochondrial dysfunction independent of substantial increases in oxidative stress, but rather marked by the diminished activities of proteins dependent on resident iron-sulfur clusters. These defects were associated with both NADPH availability and ROS accumulation, suggesting that NNT serves a specific role in mitigating the oxidation of these critical protein cofactors.<\/jats:p>","DOI":"10.1084\/jem.20191689","type":"journal-article","created":{"date-parts":[[2020,2,20]],"date-time":"2020-02-20T02:21:23Z","timestamp":1582165283000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":55,"title":["Nicotinamide nucleotide transhydrogenase regulates mitochondrial metabolism in NSCLC through maintenance of Fe-S protein function"],"prefix":"10.1084","volume":"217","author":[{"given":"Nathan P.","family":"Ward","sequence":"first","affiliation":[{"name":"Department of Cancer Physiology, Moffitt Cancer Center, Tampa, FL 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun Pyo","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Cancer Physiology, Moffitt Cancer Center, Tampa, FL 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aimee","family":"Falzone","sequence":"additional","affiliation":[{"name":"Department of Cancer Physiology, Moffitt Cancer Center, Tampa, FL 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theresa A.","family":"Boyle","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathology, Moffitt Cancer Center, Tampa, FL 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6611-6696","authenticated-orcid":true,"given":"Gina M.","family":"DeNicola","sequence":"additional","affiliation":[{"name":"Department of Cancer Physiology, Moffitt Cancer Center, Tampa, FL 1"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2020,3,20]]},"reference":[{"key":"2023072617372370400_bib1","doi-asserted-by":"publisher","first-page":"3582","DOI":"10.1091\/mbc.e12-05-0413","article-title":"The essential iron-sulfur protein Rli1 is an important target accounting for inhibition of cell growth by reactive oxygen species","volume":"23","author":"Alhebshi","year":"2012","journal-title":"Mol. 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