Nicotinamide nucleotide transhydrogenase (NNT) deficiency dysregulates mitochondrial retrograde signaling and impedes proliferation
To study the physiological roles of NADH and NADPH homeostasis in cancer, we studied the effect of NNT knockdown on physiology of SK-Hep1 cells. NNT knockdown cells show limited abilities to maintain NAD+ and NADPH levels and have reduced proliferation and tumorigenicity. There is an increased depen...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2017-08-01
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| Series: | Redox Biology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231717302781 |
| _version_ | 1818334710443540480 |
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| author | Hung-Yao Ho Yu-Ting Lin Gigin Lin Pei-Ru Wu Mei-Ling Cheng |
| author_facet | Hung-Yao Ho Yu-Ting Lin Gigin Lin Pei-Ru Wu Mei-Ling Cheng |
| author_sort | Hung-Yao Ho |
| collection | DOAJ |
| description | To study the physiological roles of NADH and NADPH homeostasis in cancer, we studied the effect of NNT knockdown on physiology of SK-Hep1 cells. NNT knockdown cells show limited abilities to maintain NAD+ and NADPH levels and have reduced proliferation and tumorigenicity. There is an increased dependence of energy production on oxidative phosphorylation. Studies with stable isotope tracers have revealed that under the new steady-state metabolic condition, the fluxes of TCA and glycolysis decrease while that of reductive carboxylation increases. Increased [α-ketoglutarate]/[succinate] ratio in NNT-deficient cells results in decrease in HIF-1α level and expression of HIF-1α regulated genes. Reduction in NADPH level leads to repression of HDAC1 activity and an increase in p53 acetylation. These findings suggest that NNT is essential to homeostasis of NADH and NADPH pools, anomalies of which affect HIF-1α- and HDAC1-dependent pathways, and hence retrograde response of mitochondria. Keywords: Transhydrogenase, Mitochondria, Metabolomics, HIF-1α, HDAC1 |
| first_indexed | 2024-12-13T14:11:51Z |
| format | Article |
| id | doaj.art-09943601f317476cb194450697c7e4ba |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-12-13T14:11:51Z |
| publishDate | 2017-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-09943601f317476cb194450697c7e4ba2022-12-21T23:42:27ZengElsevierRedox Biology2213-23172017-08-0112916928Nicotinamide nucleotide transhydrogenase (NNT) deficiency dysregulates mitochondrial retrograde signaling and impedes proliferationHung-Yao Ho0Yu-Ting Lin1Gigin Lin2Pei-Ru Wu3Mei-Ling Cheng4Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; Healthy Aging Research Center, Chang Gung University, Taoyuan 33302, Taiwan; Metabolomics Core Laboratory, Chang Gung University, Taoyuan 33302, Taiwan; Clinical Phenome Center, Chang Gung Memorial Hospital, Linkou, Taoyuan 33302, Taiwan; Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; Correspondence to: Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, 259, Wen-Hua 1st Rd., Guishan Dist., Taoyuan 33302, Taiwan.Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, TaiwanClinical Phenome Center, Chang Gung Memorial Hospital, Linkou, Taoyuan 33302, Taiwan; Department of Medical Imaging and Intervention, Imaging Core Laboratory, Institute for Radiological Research, Chang Gung Memorial Hospital at Linkou and Chang Gung University, 33302, Taoyuan, TaiwanDepartment of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 33302, TaiwanGraduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; Healthy Aging Research Center, Chang Gung University, Taoyuan 33302, Taiwan; Metabolomics Core Laboratory, Chang Gung University, Taoyuan 33302, Taiwan; Clinical Phenome Center, Chang Gung Memorial Hospital, Linkou, Taoyuan 33302, TaiwanTo study the physiological roles of NADH and NADPH homeostasis in cancer, we studied the effect of NNT knockdown on physiology of SK-Hep1 cells. NNT knockdown cells show limited abilities to maintain NAD+ and NADPH levels and have reduced proliferation and tumorigenicity. There is an increased dependence of energy production on oxidative phosphorylation. Studies with stable isotope tracers have revealed that under the new steady-state metabolic condition, the fluxes of TCA and glycolysis decrease while that of reductive carboxylation increases. Increased [α-ketoglutarate]/[succinate] ratio in NNT-deficient cells results in decrease in HIF-1α level and expression of HIF-1α regulated genes. Reduction in NADPH level leads to repression of HDAC1 activity and an increase in p53 acetylation. These findings suggest that NNT is essential to homeostasis of NADH and NADPH pools, anomalies of which affect HIF-1α- and HDAC1-dependent pathways, and hence retrograde response of mitochondria. Keywords: Transhydrogenase, Mitochondria, Metabolomics, HIF-1α, HDAC1http://www.sciencedirect.com/science/article/pii/S2213231717302781 |
| spellingShingle | Hung-Yao Ho Yu-Ting Lin Gigin Lin Pei-Ru Wu Mei-Ling Cheng Nicotinamide nucleotide transhydrogenase (NNT) deficiency dysregulates mitochondrial retrograde signaling and impedes proliferation Redox Biology |
| title | Nicotinamide nucleotide transhydrogenase (NNT) deficiency dysregulates mitochondrial retrograde signaling and impedes proliferation |
| title_full | Nicotinamide nucleotide transhydrogenase (NNT) deficiency dysregulates mitochondrial retrograde signaling and impedes proliferation |
| title_fullStr | Nicotinamide nucleotide transhydrogenase (NNT) deficiency dysregulates mitochondrial retrograde signaling and impedes proliferation |
| title_full_unstemmed | Nicotinamide nucleotide transhydrogenase (NNT) deficiency dysregulates mitochondrial retrograde signaling and impedes proliferation |
| title_short | Nicotinamide nucleotide transhydrogenase (NNT) deficiency dysregulates mitochondrial retrograde signaling and impedes proliferation |
| title_sort | nicotinamide nucleotide transhydrogenase nnt deficiency dysregulates mitochondrial retrograde signaling and impedes proliferation |
| url | http://www.sciencedirect.com/science/article/pii/S2213231717302781 |
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