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Molecular and Chemical Life Science :
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Research

Redox Biology

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Redox Biology

Organisms maintain their lives in the presence of constant interactions with their environments.  Most of the environmental factors trigger redox disturbances leading to altered function of biomolecules, which is supposed to results in pathological conditions due to aging.  Our main question is what is aging and how we age.  Our hypothesis is that impaired environmental response and subsequent smoldering inflammation are one of the important drivers of organismal aging processes.  In order to prove this hypothesis, we are focusing on the KEAP1-NRF2 system, which plays a major role in our oxidative stress response, and its related factors.  An ultimate goal of our research is achievement of healthy aging.  

The KEAP1-NRF2 system is a sulfur-employing defense mechanism; KEAP1 is a sulfur-based redox sensor, and NRF2 is a sulfur-regulating effector. Current projects in our lab are as follows.
　(1) Identifying the transcriptional regulatory mechanisms used by the redox-responsive transcription factor NRF2.
　(2) Exploring the molecular mechanisms of organismal aging induced by redox imbalance.
　(3) Understanding the molecular mechanisms of the response to exercise and its anti-aging effects. 
　(4) Exploring the role of sulfur metabolism and cancer malignancy driven by NRF2.
　(5) Exploring the regulatory mechanisms of mitochondrial function and energy metabolism controlled by NRF2.

Research Overview

We are pursuing a basic principle underlying human health.  Significance of each biochemical reaction needs to be evaluated in an integrated whole animal.  For these reasons, we conduct a lot of mouse experiments in combination with biochemical and molecular and cellular biological approaches.  
We have been working on the heterodimeric CNC-sMAF transcription factor family and found their critical roles in the maintenance of homeostasis.  Our studies revealed that the CNC-sMAF family members comprise a regulatory network that is distinct from the ones mediated by AP1 (JUN and FOS) family members.  
NRF2-sMAF heterodimer is particularly important for our health by regulating the redox balance.  Our recent achievement is the clarification of metabolic reprogramming of proliferating cells by NRF2 and anti-inflammatory function of NRF2 alleviating lethal autoimmune disease.  We also clarified that a human SNP that decreases the NRF2 activity of each individual serves as a risk factor for noise-induced hearing loss.  

 
Recent papers 
  1. Mitsuishi Y, Taguchi K, Kawatani Y, Shibata T, Nukiwa T, Aburatani H, Yamamoto M, Motohashi H.  Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell 103,760-766, 2012.
  2. Shirasaki K, Taguchi K, Unno M, Motohashi H, Yamamoto M.  Nrf2 promotes compensatory liver hypertrophy after portal vein branch ligation in mice. Hepatology 59, 2371-2382, 2014.
  3. Sekine H, Okazaki K, Ota N, Shima H, Katoh Y, Suzuki N, Igarashi K, Ito M, Motohashi H, Yamamoto M.  The Mediator subunit MED16 transduces NRF2-activating signals into antioxidant gene expression. Mol Cell Biol 36, 407-420, 2016.
  4. Honkura Y, Matsuo H, Murakami S, Sakiyama M, Mizutari K, Shiotani A, Yamamoto M, Morita I, Shinomiya N, Kawase T, Katori Y, Motohashi H.  NRF2 is a key target for prevention of noise-induced hearing loss by reducing oxidative damage of cochlea. Sci Rep 6, 19329, 2016.
  5. Kobayashi EH, Suzuki T, Funayama R, Nagashima T, Hayashi M, Sekine H, Tanaka N, Moriguchi T, Motohashi H, Nakayama K, Yamamoto M.  NRF2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. Nat Commun 7, 11624, 2016.
  6. Suzuki T, Murakami S, Biswal SS, Sakaguchi S, Harigae H, Yamamoto M, Motohashi H. Systemic activation of NRF2 alleviates lethal autoimmune inflammation in Scurfy mice. Mol Cell Biol 2017 Jul 14;37(15). pii: e00063-17.
  7. Kitamura H, Onodera Y, Murakami S, Suzuki T, Motohashi H. IL-11 contribution to tumorigenesis in an NRF2 addiction cancer model. Oncogene 36, 6315-6324, 2017.
  8. Murakami S, Suzuki T, Harigae H, Romeo PH, Yamamoto M, Motohashi H. NRF2 activation impairs quiescence and bone marrow reconstitution capacity of hematopoietic stem cells. Mol Cell Biol. 2017 Jul 3. pii: MCB.00086-17.
  9. Akaike T, Ida T, Wei FY, Nishida M, Kumagai Y, Alam MM, Ihara H, Sawa T, Matsunaga T, Kasamatsu S, Nishimura A, Morita M, Tomizawa K, Nishimura A, Watanabe S, Inaba K, Shima H, Tanuma N, Jung M, Fujii S, Watanabe Y, Ohmuraya M, Nagy P, Feelisch M, Fukuto JM, Motohashi H.  Cysteinyl-tRNA synthetase governs cysteine polysulfidation and mitochondrial bioenergetics.  Nat Commun 8, 1177, 2017.
URLs https://sites.google.com/view/motohashi-lab/home

Faculty Members

Professor MOTOHASHI Hozumi
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Transcriptional regulatory mechanisms for redox regulation and their anti-aging effects 

Research