Clinical significance of oxidative stress-induced mitochondrial dysfunction in liver tissue of biliary atresia

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K08628
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55010:General surgery and pediatric surgery-related
• Research Institution: Juntendo University
• Principal Investigator: Okazaki Tadaharu 順天堂大学, 医学部, 教授 (30265988)
• Co-Investigator(Kenkyū-buntansha): 有井 瑠美 順天堂大学, 医学部, 特任准教授 (50794418) ; 須田 一人 順天堂大学, 医学部, 准教授 (60784725)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 胆道閉鎖症 / ミトコンドリア / HSP60 / 自己肝生存 / 封入体 / 肝線維化

Outline of Final Research Achievements

Biliary atresia is a devastating infantile cholangiopathy due to obstruction of the intrahepatic bile duct and can be treated with portoenterostomy. However, a liver transplant is required in some patients due to prolonged postoperative jaundice. As there is a shortage of liver transplant donors, the development of new treatments is needed to improve liver function reserve. We investigated whether BA's hepatic functional reserve correlates with hepatocellular impaired mitochondrial function. The expression of HSP60, a mitochondrial matrix marker, was lower in BA compared with normal liver such as in patients with hepatoblastoma and other infantile cholestasis diseases. On electron microscopy, inclusion body and swelling of cristae were remarkably increased in BA. In the BA cohort, HSP60 expression was lower in the patients requiring liver transplants than native liver survivors.

Free Research Field

小児外科

Academic Significance and Societal Importance of the Research Achievements

本研究では、BA肝組織におけるミトコンドリア活性と相関するHSP60の発現が組織ダメージのない肝組織や他の乳児胆汁うっ滞疾患と比してBAで低く、かつBAの中でも経過良好な症例と比して自己肝生存しなかった症例で低いことが示された。同時に、電子顕微鏡下にミトコンドリアにダメージを示唆する所見がBAで特に強いことが見受けられ、肝組織内ミトコンドリアは肝予備能と相関する重要な因子であることが示唆された。今後、BA肝内ミトコンドリアの詳細な機能障害を検証し、かつその治療標的としての可能性を探ることで、臨床的に重要な意義が示し得ると思われる。