Cristae remodeling in apoptosis

Research Project

Project/Area Number	16K07274
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Research Field	Structural biochemistry
Research Institution	Kyushu University
Principal Investigator	OTERA HIDENORI 九州大学, 医学研究院, 助教 (40380612)
Project Period (FY)	2016-04-01 – 2019-03-31
Project Status	Completed (Fiscal Year 2018)
Budget Amount *help	¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000) Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000) Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000) Fiscal Year 2016: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Keywords	ミトコンドリア / アポトーシス / クリステ / ミトコンドリア形態
Outline of Final Research Achievements	Mitochondrial fission facilitates release of cytochrome c from intra-critae space into the cytoplasm during intrinsic apoptosis, although how mitochondrial fission factors Drp1 and its mitochondrial receptors Mff, MiD49 and MiD51 are involved in this reaction remains elusive. In spite of this antiapoptotic phenotype, OPA1 oligomers that are generally thought to resist cytochrome c release by stabilizing tight cristae structures were disassembled with similar kinetics as wild-type cells upon apoptosis induction. Disruption of pre-existing cristae by OPA1 depletion restored cytochrome c release in MiD49/51-KO cells. Re-expression of MiD51 mutant revealed that Drp1 recruitment is required for MiD51-regulating cytochrome c release. Thus, Drp1-dependent mitochondrial fission through MiD49 and MiD51 is epistatic to cristae remodeling and function as essential gatekeepers for intrinsic apoptosis.
Academic Significance and Societal Importance of the Research Achievements	アポトーシスは抗がん剤によるがん細胞死に必須な反応でありその執行にはミトコンドリア構造変化が大きく関与している。今回アポトーシスにおいてミトコンドリアクリステ構造が分裂と共益することが必須な反応であることを明らかにした。この反応の素過程を詳細に解析するための試験管内ミトコンドリア分裂系を確立した。これにより各反応に関わる分子同定がなされれば新規抗がん剤開発に大いに貢献するものと考えている。