Role of MITOL in mitochondrial dynamics

2016 Fiscal Year Final Research Report

• Project/Area Number: 26293072
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Tokyo University of Pharmacy and Life Science
• Principal Investigator: YANAGI Shigeru 東京薬科大学, 生命科学部, 教授 (60252003)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: ミトコンドリア / ユビキチンリガーゼ

Outline of Final Research Achievements

Previously, we identified the mitochondrial ubiquitin ligase MITOL and demonstrated that MITOL mediates lysine-63-linked polyubiquitin chain addition to Mfn2 and induces the mitochondria-associated ER membrane (MAM) formation through Mfn2 oligomerization. However, the physiological roles of MITOL in MAM structure and function in vivo remain unknown. In this study, I obserbed the MAM structure in MITOL-KO brain using 3D-SEM analysis, and found that MITOL regulates mitochondrial morphology and cardiolipin biogenesis through Mfn2-dependent MAM formation in vivo. Furthermore, we found that MITOL inhibits ER stress-induced apoptosis by IRE1α ubiquitylation at the MAM. MITOL adds lysine (K) 63-linked polyubiquitin chain to K481 of IRE1α, thereby preventing hyper-oligomerization of IRE1α and regulated IRE1α-dependent decay of mRNA activity. Our findings provide a novel concept that mitochondria determine cell fate under ER stress through IRE1α regulation by MITOL at the MAM.

Free Research Field

生化学