Nicotinamide nucleotide transhydrogenase regulates mitochondrial metabolism in NSCLC through maintenance of Fe-S protein function
Open Access
- 20 March 2020
- journal article
- research article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 217 (6)
- https://doi.org/10.1084/jem.20191689
Abstract
Human lung tumors exhibit robust and complex mitochondrial metabolism, likely precipitated by the highly oxygenated nature of pulmonary tissue. 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.Keywords
Funding Information
- V Foundation for Cancer Research (V2017-015)
- National Institutes of Health (R37-CA230042)
- Hope Funds for Cancer Research
- AACR-Takeda Oncology Lung Cancer Research Fellowship (19-40-38-KANG)
- Moffitt Cancer Center (NCI, P30-CA076292)
- Moffitt Foundation
- Florida Bankhead-Coley (06BS-02–9614)
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