Molecular mechanism of osteocyte senescence by mitochondrial retrograde signaling
| Project/Area Number |
20H03583
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 52010:General internal medicine-related
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| Research Institution | National Center for Geriatrics and Gerontology |
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Principal Investigator |
Shimizu Takahiko 国立研究開発法人国立長寿医療研究センター, 研究所 老化ストレス応答研究プロジェクトチーム, プロジェクトリーダー (40301791)
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| Co-Investigator(Kenkyū-buntansha) |
澁谷 修一 国立研究開発法人国立長寿医療研究センター, 研究所 老化ストレス応答研究プロジェクトチーム, 研究員 (70866342)
渡辺 憲史 国立研究開発法人国立長寿医療研究センター, 研究所 老化ストレス応答研究プロジェクトチーム, 研究員 (90866766)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2022: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2020: ¥8,970,000 (Direct Cost: ¥6,900,000、Indirect Cost: ¥2,070,000)
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| Keywords | ミトコンドリア / 骨細胞 / ストレス応答 / 細胞老化 |
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| Outline of Research at the Start |
加齢に伴い、骨組織は緩やかに骨量が減少し、多様な生理機能が失われる。近年、骨組織の主要細胞である骨細胞の加齢変化に細胞老化の寄与が示され、骨細胞老化と骨の加齢変化の関係性が注目されている。申請者らは、骨細胞でミトコンドリア機能不全がストレス応答転写因子ATF4を核集積させる逆行性シグナルによって、細胞老化様変化と骨関連遺伝子群の発現変化を誘導し、加齢様骨量減少をもたらすことを明らかにしつつある。本研究では、ミトコンドリア機能低下に応答するATF4を含むミトコンドリア逆行性関連因子の分子関連を調べ、骨細胞を起点とした骨老化の分子メカニズム解明を目指す。
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| Outline of Final Research Achievements |
During the process of age-related bone loss, osteocyte mitochondrial dysfunction activates a retrograde integrative stress response-ATF4 axis, which induces nuclear structural changes through reduction of nuclear lamina proteins (Lamin A and Lamin B) and upregulation of sclerostin, a regulator of bone metabolism. This is one of the molecular mechanisms mediating mitochondrial retrograde signaling and osteocyte senescence.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究によってミトコンドリア機能不全を起因とした核膜構造異常と骨代謝制御不全の関連性が明らかとなった。加齢依存的に骨量減少が起こる分子機構の一端が明らかになったことから学術的意義が高い研究であると言える。さらにこの研究成果は骨量減少の予防や治療戦略を立てる為に重要であり、ロコモティブシンドローム発症予防に貢献できる可能性があり社会的意義の大きな研究であると考えられる。
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Report
(4 results)
Research Products
(81 results)
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[Journal Article] Empagliflozin improves cardiac mitochondrial function and survival through energy regulation in a murine model of heart failure.2022
Author(s)
Shiraki, A., Jun-ichi Oyama, J., Shimizu, T., Nakashima, T., Yokota, T., Node, K.
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Journal Title
Eur J Pharmacol
Volume: 931
Pages: 175194-175194
DOI
Related Report
Peer Reviewed
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[Journal Article] Lysine-targeting inhibition of amyloid β oligomerization by a green perilla-derived metastable chalcone in vitro and in vivo.2022
Author(s)
Murakami, K., Sakaguchi, Y., Taniwa, K., Izuo, N., Hanaki, M., Kawase, T., Hirose, K., Nagao, C., Mizoguchi, K., Shimizu, T., Irie, K.
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Journal Title
RSC Chem. Biol.
Volume: 3
Issue: 12
Pages: 1380-1396
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Symposium25-42022
Author(s)
清水孝彦
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Journal Title
Japanese Journal of Physical Fitness and Sports Medicine
Volume: 71
Issue: 1
Pages: 118-118
DOI
NAID
ISSN
0039-906X, 1881-4751
Related Report
Open Access
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[Journal Article] SOD2 in skeletal muscle: New insights from an inducible deletion model.2021
Author(s)
Zhuang, A., Yang, C., Liu, Y., Tan, Y., Bond, S.T., Walker, S., Sikora, T., Laskowski, A., Sharma, A., de Haan, J.B., Meikle, P.J., Shimizu, T., Coughlan, M.T., Calkin, A.C., Drew, B.G.
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Journal Title
Redox Biology
Volume: 47
Pages: 102135-102135
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Neuron-specific mitochondrial oxidative stress results in epilepsy, glucose dysregulation and a striking astrocyte response.2021
Author(s)
Fulton, R.E., Pearson-Smith, J.N., Huynh, C.Q., Fabisiak, T., Liang, L., Aivazidis, S., High, B.A., Buscaglia, G., Corrigan, T., Valdez, R., Danis, E., Shimizu, T., and Patel, M.N.
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Journal Title
Neurobiol. Dis.
Volume: 158
Pages: 105470-105470
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] SOD1 deficiency alters gastrointestinal microbiota and metabolites in mice2020
Author(s)
Sagi, H., Shibuya, S., Kato, T., Nakanishi, Y., Tsuboi, A., Moriya, S., Ohno, H., Miyamoto, H., Kodama, H., Shimizu, T.
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Journal Title
Exp. Gerontol.
Volume: 130
Pages: 110795-110795
DOI
Related Report
Peer Reviewed
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[Journal Article] The effects of 3% diquafosol sodium eye drops on tear functions and ocular surface of the Cu, Zn-superoxide dismutase-1 (Sod1) knock out mice treated with antiglaucoma eye medications2020
Author(s)
Yagi-Yaguchi, Y., Kojima, T., Higa, K., Dogru, M.*, Ibrahim, O., Shimizu, T., Tsubota, K. Shimazaki, J.
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Journal Title
Diagnostics
Volume: 10
Issue: 1
Pages: 20-20
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] SOD2 deficiency in cardiomyocytes defines defective mitochondrial bioenergetics as a cause of lethal dilated cardiomyopathy2020
Author(s)
Sharma, S., Bhattarai, S., Ara, H., Sun G., St. Clair, D.K., Bhuiyan, S., Kevil, C., Watts, M.N., Dominic, P., Shimizu, T., McCarthy, K.J., Sun, H., Panchatcharam, M.
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Journal Title
Redox Biology
Volume: 37
Pages: 101740-101740
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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