| Budget Amount *help |
¥16,120,000 (Direct Cost: ¥12,400,000、Indirect Cost: ¥3,720,000)
Fiscal Year 2016: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2015: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2014: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
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| 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.
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