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.
Highlights
Metabolic rewiring facilitates the diversion of intermediate metabolites into pathways that supply the macromolecular determinants of the unbridled growth associated with human tumors
P53 deletion abrogated the effects of Nicotinamide nucleotide transhydrogenase (NNT) expression on lung tumor formation in this model, with substantial tumor burden present at the experimental endpoint regardless of NNT status (Fig. 1 D)
We found that NNT knockdown significantly reduced ACO2 activity in those non-small cell lung cancer (NSCLC) lines with NNT expression (Fig. 3 E)
Summary
Metabolic rewiring facilitates the diversion of intermediate metabolites into pathways that supply the macromolecular determinants of the unbridled growth associated with human tumors. Non-small cell lung cancer (NSCLC) exhibits a simultaneous engagement of both glycolytic and oxidative metabolism (Fan et al, 2009) This increase in mitochondrial oxidation is supported by enhanced expression of pyruvate carboxylase, which provides auxiliary entry of glucose carbon into the TCA cycle in addition to that via pyruvate dehydrogenase (PDH) (Sellers et al, 2015, Davidson et al, 2016). These activities support glucose oxidation in human lung tumors that exceeds that of normal adjacent lung (Hensley et al, 2016). Human lung tumors exhibit remarkable plasticity in oxidative fuel usage that is correlated with oxygen tension, indicating robust mitochondrial function (Hensley et al, 2016, Faubert et al, 2017)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
