The research of the association between the pathogenesis of sensorineural hearing loss and endoplasmic reticulum stress caused by reductive stress induced by sustained activation of NRF2.

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K16838
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56050:Otorhinolaryngology-related
• Research Institution: Tohoku University
• Principal Investigator: Kishino Akihiro 東北大学, 加齢医学研究所, 分野研究員 (80825307)
• Project Period (FY): 2021-04-01 – 2023-03-31
• Keywords: NRF2 / 硫黄代謝 / ミトコンドリア膜電位 / シスチン / シスチンパースルフィド

Outline of Final Research Achievements

The purpose of this study was to elucidate the molecular mechanism by which NRF2 activates mitochondrial function. Extracellular addition of glutathione persulfide increased intracellular cysteine persulfide, and enhanced mitochondrial membrane potential and increased oxygen consumption were observed. Activation of NRF2 similarly enhanced mitochondrial membrane potential and increased oxygen consumption. Simultaneous with NRF2 activation, either suppression of the expression of the NRF2 target gene cystine transporter xCT or inhibition of CARS2 canceled the enhancement of mitochondrial membrane potential and oxygen consumption. Thus, NRF2 increases cellular cystine uptake through increased expression of xCT and increases cysteine persulfide production to activate mitochondrial function.

Free Research Field

耳鼻咽喉科

Academic Significance and Societal Importance of the Research Achievements

ミトコンドリアの生理学的に重要な細胞小器官であり、ミトコンドリアの機能不全は老化や様々な疾患と関連している。本研究では、NRF2がxCTを介してシスチンの取り込みを促進し、ミトコンドリアにおける活性硫黄種の産生と代謝を促進することによりその機能を増強することが明らかになった。NRF2のミトコンドリア機能の活性化の分子機構を明らかにすることによって、今後様々な疾患の病態解明に貢献し得る。