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REVIEW: Transcription Factor Nrf2 and Mitochondria – Friends or Foes in the Regulation of Aging Rate

Gregory A. Shilovsky1,2,3,a,a* and Vasily V. Ashapkin1

1Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia

2Faculty of Biology, Lomonosov Moscow State University, 119234 Moscow, Russia

3Institute for Information Transmission Problems, Russian Academy of Sciences, 127051 Moscow, Russia

* To whom correspondence should be addressed.

Received October 17, 2022; Revised November 24, 2022; Accepted November 25, 2022
At the first sight, the transcription factor Nrf2 as a master regulator of cellular antioxidant systems, and mitochondria as the main source of reactive oxygen species (ROS), should play the opposite roles in determining the pace of aging. However, since the causes of aging cannot be confined to the oxidative stress, the role of Nrf2 role cannot be limited to the regulation of antioxidant systems, and moreover, the role of mitochondria is not confined to the ROS production. In this review, we discussed only one aspect of this problem, namely, the molecular mechanisms of interaction between Nrf2 and mitochondria that influence the rate of aging and the lifespan. Experimental data accumulated so far show that the Nrf2 activity positively affects both the mitochondrial dynamics and mitochondrial quality control. Nrf2 influences the mitochondrial function through various mechanisms, e.g., regulation of nuclear genome-encoded mitochondrial proteins and changes in the balance of ROS or other metabolites that affect the functioning of mitochondria. In turn, multiple regulatory proteins functionally associated with the mitochondria affect the Nrf2 activity and even form mutual regulatory loops with Nrf2. We believe that these loops enable the fine-tuning of the cellular redox balance and, possibly, of the cellular metabolism as a whole. It has been commonly accepted for a long time that all mitochondrial regulatory signals are mediated by the nuclear genome-encoded proteins, whereas the mitochondrial genome encodes only a few respiratory chain proteins and two ribosomal RNAs. Relatively recently, mtDNA-encoded signal peptides have been discovered. In this review, we discuss the data on their interactions with the nuclear regulatory systems, first of all, Nrf2, and their possible involvement in the regulation of the aging rate. The interactions between regulatory cascades that link the programs ensuring the maintenance of cellular homeostasis and cellular responses to the oxidative stress are a significant part of both aging and anti-aging programs. Therefore, understanding these interactions will be of great help in searching for the molecular targets to counteract aging-associated diseases and aging itself.
KEY WORDS: Nrf2, mitochondria, aging, lifespan, oxidative stress, aging diseases, antioxidants

DOI: 10.1134/S0006297922120057