Adaptation to Environmental stress and quality control of myocardial mitochondria by reactive sulfur species
| Project/Area Number |
17K15464
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
薬理系薬学
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| Research Institution | Kyushu University (2018)
National Institute for Physiological Sciences (2017) |
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Principal Investigator |
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| Project Period (FY) |
2017-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Keywords | レドックス / 心臓リモデリング / ミトコンドリア品質 / 活性イオウ / 親電子物質 / 心臓 / ストレス適応 / 環境化学物質 / ミトコンドリア / 心疾患 / 環境ストレス |
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| Outline of Final Research Achievements |
We found that abnormal quality control (hyperfission) of cardiac mitochondria triggered the disruption of cardiac homeostasis. We identified that filamin A act as a guanine nucleotide exchange factor for Drp1, mitochondrial fission-accelerating factor. Pathological interaction of Drp1-filamin-actin at mitochondrial fission induced mitochondrial hyperfission-associated myocardial senescence, resulting in cardiac dysfunctions. Reactive sulfur-dependent polysulfidation of Drp1 negatively regulated the interaction with filamin A, and environmental electrophiles such as a methylmercury promoted depolysulfidation and activation of Drp1. Depolysulfidation of Drp1 by electrophiles increased cardiac fragility to mechanical load through filamin-dependent mitochondrial hyperfission.
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| Academic Significance and Societal Importance of the Research Achievements |
心疾患による死亡者数は年間約20万に上がり、これはがんに次ぐ死因となっている。心不全患者の5年生存率は未だ50%であり、新しいコンセプトに基づいた薬の開発が必要とされている。我々は心筋ミトコンドリアの品質異常が心機能低下の引き金になることを見出し、ミトコンドリアの品質を改善する既承認薬シルニジピンを同定した。さらに、シルニジピンは環境化学物質曝露による心疾患リスク上昇に対しても改善効果を示すことをマウス動物実験モデルから明らかにした。これらの成果はミトコンドリア機能保護という新しいコンセプトに基づいた心不全治療薬開発に貢献すると期待される。
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Report
(3 results)
Research Products
(29 results)
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[Journal Article] Hypoxia-induced interaction of filamin with Drp1 causes mitochondrial hyperfission-associated myocardial senescence2018
Author(s)
Nishimura A, Shimauchi T, Tanaka T, Shimoda K, Toyama T, Kitajima N, Ishikawa T, Shindo N, Numaga-Tomita T, Yasuda S, Sato Y, Kuwahara K, Kumagai Y, Akaike T, Ide T, Ojida A, Mori Y, Nishida M.
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Journal Title
Science Signaling
Volume: 11
Pages: 5185-5185
DOI
Related Report
Peer Reviewed / Open Access
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