Modulation of mitochondrial function by reactive sulfur signaling

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K21565
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 52:General internal medicine and related fields
• Research Institution: Tohoku University
• Principal Investigator: Wei Fan-Yan 東北大学, 加齢医学研究所, 教授 (90555773)
• Co-Investigator(Kenkyū-buntansha): 小川 亜希子 東北大学, 加齢医学研究所, 助教 (00868565)
• Project Period (FY): 2020-07-30 – 2022-03-31
• Keywords: RNA修飾 / ミトコンドリア / 代謝

Outline of Final Research Achievements

Mitochondrial disease is a rare genetic disease characterized by the catastrophic impairment of mitochondrial metabolism caused by pathogenic mutations in mitochondrial DNA or nuclear DNA. However, there is no effective treatment for mitochondrial disease. Recently, our research has discovered that the reactive sulfur species-mediated signaling is involved in the pathogenesis of mitochondrial disease. We found that the reactive sulfur species donate sulfur atoms to mitochondrial tRNA to form tRNA thiolation. Decrease of mitochondrial tRNA thiolation is responsible for the alteration of mitochondrial protein translation and the subsequent metabolic dysfunction. In the current study, we performed a comprehensive genetic screening using shRNA library targeting genes that are related to mitochondrial functions. We identified that knockdown of several genes can lead to the recovery of mitochondrial membrane potential and cell growth in a mitochondrial disease cell model.

Free Research Field

病態生理学

Academic Significance and Societal Importance of the Research Achievements

本研究により、活性硫黄に由来するシグナルへの介入がミトコンドリアの機能回復につながることが示された。これにより、将来的に同調節因子を標的とする革新的なミトコンドリア病治療薬の創出、そしてミトコンドリア病の根本的な改善が可能であり、難病治療にブレークスルーをもたらすことが期待される。