Emerging evidence for crosstalk between Nrf2 and mitochondria in physiological homeostasis and in heart disease

  • Michiko Tsushima
  • Jun Liu
  • Wataru Hirao
  • Hiromi Yamazaki
  • Hirofumi Tomita
  • Ken ItohEmail author


Nrf2 regulates redox homeostasis in cells by coordinately regulating a range of antioxidant enzymes and proteins. An increase in oxidative stress is one of the hallmarks of aging, and Nrf2 protein levels and activity decrease with aging. Decreased mitochondrial functions, such as decreased ATP production, also occur with aging, leading to the increased generation of reactive oxygen species (ROS) and oxidative stress. Thus, understanding the relationships between Nrf2 and the mitochondria is important for clarifying the regulatory mechanisms of aging. It is becoming clear that Nrf2 is activated in a tissue-specific manner in response to mitochondrial or NADPH oxidase-generated ROS. As the heart consists of postmitotic cells that utilize ATP produced mainly by mitochondrial oxidative phosphorylation, cardiomyocytes are equipped with highly sophisticated mitochondrial quality control mechanisms. Consistent with these findings, it has been reported that Nrf2 in the heart is regulated via a specific translational mechanism and that Nrf2 activation confers cardioprotective effects in various disease models. Thus, Nrf2 is a promising target for anti-aging strategies to combat age-related heart diseases, such as age-related cardiomyopathy.


Nrf2 Mitocondria Reactive oxygen species Mitohormesis Heart 



We thank Drs. Junsei Mimura and Shuya Kasai for the critical reading and suggestions for the manuscript. This work was supported by MEXT/JSPS KAKENHI Grant No. (26111010) and a Hirosaki University Institutional Research Grant.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interest.


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© The Pharmaceutical Society of Korea 2019

Authors and Affiliations

  1. 1.Department of Stress Response Science, Center for Advanced Medical ResearchHirosaki University Graduate School of MedicineHirosakiJapan
  2. 2.Department of Cardiology and NephrologyHirosaki University Graduate School of MedicineHirosakiJapan

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