Search for new mechanisms by which mitochondria control autophagy and metabolites of aging-related diseases
| Project/Area Number |
18K15421
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 52010:General internal medicine-related
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| Research Institution | Kyushu University |
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Principal Investigator |
Yagi Mikako 九州大学, 医学研究院, 助教 (70536135)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | ミトコンドリア / p32 / NAD / 老化 / NAD合成 / 心筋症 / HIF1α / GAPDH / mitochondria / HIF1 / lysosome / autophagy / knockout mouse / オートファジー / ノックアウトマウス |
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| Outline of Final Research Achievements |
Heart specific p32 knockout mice developed dilated cardiomyopathy at an early stage and died in about 500 days. We considered that the main cause of shortened lifespan is decreased lysosomal function. The mechanism is that the expression of the salvage pathway enzyme Nmnat3, one of the NAD synthesis pathways, is reduced due to the decrease in mitochondrial function, and as a result, the amount of NAD synthesis is also reduced, due to the glycolytic enzymes GAPDH and PGK localized lysosomal outer membrane. ATP dependent lysosomal proton pump, so decreased ATP caused a decrease in lysosomal activity. We also demonstrated that Nmnat3 is regulated by the transcription factor HIF1α.
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| Academic Significance and Societal Importance of the Research Achievements |
老化に伴う多くの疾患はミトコンドリア機能、オートファジー機能, 血中NAD量低下が関与すると考えられているがその詳細な分子機構は明らかではない。今回我々はミトコンドリア機能障害マウスを用いて、心臓においてミトコンドリアを介したリソソーム機能制御の新機構を発見した。リソソーム活性にはNAD＋を基質として解糖系酵素(GAPDH・PGK)によって産生されるATPが関与していると世界で初めて報告した。老化と共に減少するNAD＋を補うことで老化と共に発症する疾患の予防・治療に繋がることがわかってきている。したがって新機構の解明によって治療戦略の可能性が広がることになるだろう。
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Report
(4 results)
Research Products
(7 results)
