Nrf2 impacts cellular bioenergetics by controlling substrate availability for mitochondrial respiration
Kira M. Holmström,Liam Baird,Ying Zhang,Iain P. Hargreaves,Annapurna Chalasani,John M. Land,Lee Stanyer,Masayuki Yamamoto,Albena T. Dinkova-Kostova,Albena T. Dinkova-Kostova,Andrey Y. Abramov +10 more
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TLDR
A novel role is demonstrated for Nrf2 in directly regulating mitochondrial bioenergetics in murine neurons and embryonic fibroblasts through modulating the availability of substrates for mitochondrial respiration and the importance of efficient energy metabolism in NRF2-mediated cytoprotection.Abstract:
Transcription factor Nrf2 and its repressor Keap1 regulate a network of cytoprotective genes involving more than 1% of the genome, their best known targets being drug-metabolizing and antioxidant genes. Here we demonstrate a novel role for this pathway in directly regulating mitochondrial bioenergetics in murine neurons and embryonic fibroblasts. Loss of Nrf2 leads to mitochondrial depolarisation, decreased ATP levels and impaired respiration, whereas genetic activation of Nrf2 increases the mitochondrial membrane potential and ATP levels, the rate of respiration and the efficiency of oxidative phosphorylation. We further show that Nrf2-deficient cells have increased production of ATP in glycolysis, which is then used by the F1Fo-ATPase for maintenance of the mitochondrial membrane potential. While the levels and in vitro activities of the respiratory complexes are unaffected by Nrf2 deletion, their activities in isolated mitochondria and intact live cells are substantially impaired. In addition, the rate of regeneration of NADH after inhibition of respiration is much slower in Nrf2-knockout cells than in their wild-type counterparts. Taken together, these results show that Nrf2 directly regulates cellular energy metabolism through modulating the availability of substrates for mitochondrial respiration. Our findings highlight the importance of efficient energy metabolism in Nrf2-mediated cytoprotection.read more
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The Nrf2 regulatory network provides an interface between redox and intermediary metabolism
TL;DR: Observations suggest Nrf2 directs metabolic reprogramming during stress, which would enable the factor to orchestrate adaptive responses to diverse forms of stress.
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Transcriptional Regulation by Nrf2
TL;DR: The different modes of regulation of Nrf2 activity are reviewed and the current knowledge of NRF2-mediated transcriptional control is reviewed to provide insight into mechanisms of disease and instruct new treatment strategies.
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NRF2 and the Hallmarks of Cancer.
TL;DR: The roles of NRF2 in the hallmarks of cancer are explored, indicating both tumor suppressive and tumor-promoting effects.
Journal ArticleDOI
Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases
Antonio Cuadrado,Ana I. Rojo,Geoffrey Wells,John D. Hayes,Sharon P. Cousin,William L. Rumsey,Attucks Otis Clinton,Stephen Franklin,Anna-Liisa Levonen,Thomas W. Kensler,Albena T. Dinkova-Kostova,Albena T. Dinkova-Kostova +11 more
TL;DR: An overview of the physiological and pathological roles of NRF2 is provided, emerging pharmacological modulators of theNRF2–KEAP1 axis are presented and associated drug development challenges are highlighted.
Journal ArticleDOI
The emerging role of Nrf2 in mitochondrial function.
TL;DR: Nrf2 is a prominent player in supporting the structural and functional integrity of the mitochondria, and this role is particularly crucial under conditions of stress.
References
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Measurement of protein using bicinchoninic acid
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An nrf2/small maf heterodimer mediates the induction of phase ii detoxifying enzyme genes through antioxidant response elements
Ken Itoh,Tomoki Chiba,Satoru Takahashi,Tetsuro Ishii,Kazuhiko Igarashi,Yasutake Katoh,Tatsuya Oyake,Norio Hayashi,Kimihiko Satoh,Ichiro Hatayama,Masayuki Yamamoto,Yo-ichi Nabeshima +11 more
TL;DR: It is demonstrated that Nrf2 is essential for the transcriptional induction of phase II enzymes and the presence of a coordinate transcriptional regulatory mechanism for phase II enzyme genes and the nrf2-deficient mice may prove to be a very useful model for the in vivo analysis of chemical carcinogenesis and resistance to anti-cancer drugs.
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Cell Survival Responses to Environmental Stresses Via the Keap1-Nrf2-ARE Pathway
TL;DR: The development of Nrf2 knockout mice has provided key insights into the toxicological importance of this pathway, and this review highlights the key elements in this adaptive response to protection against acute and chronic cell injury provoked by environmental stresses.