Molecular mechanism regulating intracellular and organismal magnesium levels

• Project/Area Number: 26291042
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Cell biology
• Research Institution: Osaka University
• Principal Investigator: MIKI Hiroaki 大阪大学, 微生物病研究所, 教授 (80302602)
• Co-Investigator(Renkei-kenkyūsha): YAMAZAKI Daisuke 大阪大学, 微生物病研究所, 准教授 (50422415) ; FUNATO Yosuke 大阪大学, 微生物病研究所, 助教 (60505775)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥16,250,000 (Direct Cost: ¥12,500,000、Indirect Cost: ¥3,750,000); Fiscal Year 2016: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2015: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
• Keywords: マグネシウム / ストレス / 癌 / 循環器・高血圧

Outline of Final Research Achievements

In this research project, I performed multiple analyses on CNNM Mg2+ transporter proteins, using mammalian cultured cells, mice, and nematodes. As a result, I elucidated that CNNM proteins play important roles in regulating intracellular Mg2+ levels and Mg2+ absorption in the intestine. Intracellular Mg2+ levels affected the energy status of cells, which had a significant impact on mTOR signaling. Moreover, I found that dysregulation of Mg2+ levels caused sperm malfunction and imbalance of proliferation/differentiation of intestinal epithelia.

Research Products

• [Int'l Joint Research] McGill大学(カナダ)
• [Int'l Joint Research] McGill University(カナダ)
• [Journal Article] Phosphatase of regenerating liver maintains cellular magnesium homeostasis (2018)
  • Author(s): Yoshida A, Funato Y, Miki H
  • Journal Title: Biochem J. Volume: 475 Issue: 6 Pages: 1129-1139
  • DOI: 10.1042/bcj20170756
  • Peer Reviewed
• [Journal Article] CrossTalk proposal: CNNM proteins are Na+/Mg2+exchangers playing a central role in transepithelial Mg2+(re)absorption (2018)
  • Author(s): Funato Y, Furutani K, Kurachi Y, Miki H
  • Journal Title: J Physiol. Volume: 596 Issue: 5 Pages: 743-746
  • DOI: 10.1113/jp275248
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Visualization of long-term Mg2+ dynamics in apoptotic cells using a novel targetable fluorescent probe (2017)
  • Author(s): Matsui Y, Funato Y, Imamura H, Miki H, Mizukami S, Kikuchi K
  • Journal Title: Chem Sci. Volume: 8 Issue: 12 Pages: 8255-8264
  • DOI: 10.1039/c7sc03954a
  • Peer Reviewed / Open Access
• [Journal Article] Renal function of cyclin M2 Mg2+ transporter maintains blood pressure. (2017)
  • Author(s): Funato Y, Yamazaki D, Miki H.
  • Journal Title: J Hypertens. Volume: 35 Issue: 3 Pages: 585-592
  • DOI: 10.1097/hjh.0000000000001211
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Phosphocysteine in the PRL-CNNM pathway mediates magnesium homeostasis. (2016)
  • Author(s): Gulerez I, Funato Y, Wu H, Yang M, Kozlov G, Miki H, Gehring K.
  • Journal Title: EMBO Rep. Volume: 17 Issue: 12 Pages: 1890-1900
  • DOI: 10.15252/embr.201643393
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Mg2+ Extrusion from Intestinal Epithelia by CNNM Proteins Is Essential for Gonadogenesis via AMPK-TORC1 Signaling in Caenorhabditis elegans. (2016)
  • Author(s): Ishii T, Funato Y, Hashizume O, Yamazaki D, Hirata Y, Nishiwaki K, Kono N, Arai H, Miki H.
  • Journal Title: PLoS Genet. Volume: 12 Issue: 8 Pages: e1006276-e1006276
  • DOI: 10.1371/journal.pgen.1006276
  • Peer Reviewed / Open Access
• [Journal Article] Complementary role of CNNM2 in sperm motility and Ca(2+) influx during capacitation. (2016)
  • Author(s): Yamazaki D, Funato Y, Miyata H, Ikawa M, Miki H.
  • Journal Title: Biochem Biophys Res Commun. Volume: 474 Issue: 3 Pages: 441-446
  • DOI: 10.1016/j.bbrc.2016.05.001
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The Mg2+ transporter CNNM4 regulates sperm Ca2+ homeostasis and it is essential for reproduction (2016)
  • Author(s): Daisuke Yamazaki, Haruhiko Miyata, Yosuke Funato, Yoshitaka Fujihara, Masahito Ikawa, Hiroaki Miki
  • Journal Title: Journal of Cell Science Volume: 未定 Issue: 9 Pages: 1940-1949
  • DOI: 10.1242/jcs.182220
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Basolateral sorting of the Mg2+ transporter CNNM4 requires interaction with AP-1A and AP-1B. (2014)
  • Author(s): Hirata Y, Funato Y, Miki H.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 455 Issue: 3-4 Pages: 184-189
  • DOI: 10.1016/j.bbrc.2014.10.138
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Membrane Protein CNNM4-Dependent Mg2+ Efflux Suppresses Tumor Progression (2014)
  • Author(s): Yosuke Funato, Daisuke Yamazaki, Shin Mizukami, Lisa Du, Kazuya Kikuchi, Hiroaki Miki
  • Journal Title: J. Clin. Invest. Volume: 124 Issue: 12 Pages: 5398-5410
  • DOI: 10.1172/jci76614
  • Peer Reviewed
• [Journal Article] Reconstruction of insulin signal flow from phosphoproteome and metabolome data (2014)
  • Author(s): Yugi, K., Kubota, H., Toyoshima, Y., Noguchi, R., Kawata, K., Komori, Y., Uda, S., Kunida, K., Tomizawa, Y., Funato, Y., Miki, H., Matsumoto, M., Nakayama, K.I., Kashikura, K., Endo, K., Ikeda, K., Soga, T., Kuroda, S.
  • Journal Title: Cell Rep. Volume: 8 Issue: 4 Pages: 1171-1183
  • DOI: 10.1016/j.celrep.2014.07.021
  • NAID: 120005537752
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Mg2+-dependent interactions of ATP with the cystathionine-β-synthase (CBS) domains of a magnesium transporter. (2014)
  • Author(s): Hirata Y, Funato Y, Takano Y, Miki H.
  • Journal Title: J. Biol. Chem. Volume: 289 Issue: 21 Pages: 14731-14739
  • DOI: 10.1074/jbc.m114.551176
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] PRL/CNNM複合体によるMg2+排出の調節とPRLのCysリン酸化 (2018)
  • Author(s): 三木 裕明
  • Organizer: 生体分子コバレント修飾の革新的解析拠点形成 シンポジウム
  • Invited
• [Presentation] Mg2+の不足によるPRLの転写活性化 (2017)
  • Author(s): Yoshida A, Funato Y, Miki H
  • Organizer: 2017年度生命科学系学会合同年次大会
• [Presentation] Mg2+トランスポーターCNNM4は大腸での発がんを抑制する (2017)
  • Author(s): Yamazaki D, Hasegawa A, Funato Y, Miki H
  • Organizer: 2017年度生命科学系学会合同年次大会
• [Presentation] Mg2+トランスポーターCNNMは線虫でROSレベルと寿命を調節する (2017)
  • Author(s): Hashizume O, Funato Y, Miki H
  • Organizer: 2017年度生命科学系学会合同年次大会
• [Presentation] PRLによる酸性微小環境への適応 (2017)
  • Author(s): Funato Y, Yoshida A, Yamazaki D, Miki H
  • Organizer: 2017年度生命科学系学会合同年次大会
• [Presentation] がんの浸潤運動におけるPRLの役割 (2017)
  • Author(s): 船戸洋佑, 山崎大輔, 吉田篤, 三木裕明
  • Organizer: 第69回日本細胞生物学会大会
  • Invited
• [Presentation] がんの悪性化と酸性環境適応の分子機構 (2017)
  • Author(s): 船戸洋佑, 山崎大輔, 吉田篤, 三木裕明
  • Organizer: 第44回日本毒性学会学術年会
  • Invited
• [Presentation] CNNM magnesium transporters in health and disease (2017)
  • Author(s): Yosuke Funato, Daisuke Yamazaki, Hiroaki Miki
  • Organizer: IUPS 38th world congress
  • Int'l Joint Research / Invited
• [Presentation] PRLによる細胞内Mg2+量の調節とその破綻によるがん悪性化 (2016)
  • Author(s): 船戸 洋佑、山崎 大輔、三木 裕明
  • Organizer: 第89回日本生化学会大会シンポジウム
  • Place of Presentation: 仙台
  • Year and Date: 2016-09-25
  • Invited
• [Presentation] PRLによるがん悪性化とpH依存性の細胞死 (2016)
  • Author(s): 三木 裕明
  • Organizer: 第25回日本Cell Death学会学術集会シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2016-09-09
  • Invited
• [Presentation] PRLによる細胞内マグネシウムイオン量のレドックス制御 (2016)
  • Author(s): 船戸 洋佑、山崎 大輔、三木 裕明
  • Organizer: 第43回日本毒性学会学術年会シンポジウム
  • Place of Presentation: 名古屋
  • Year and Date: 2016-06-29
  • Invited
• [Presentation] PRLによるがん悪性化と上皮組織内の細胞間相互作用 (2016)
  • Author(s): 船戸 洋佑、山崎 大輔、三木 裕明
  • Organizer: 第68回日本細胞生物学会大会シンポジウム
  • Place of Presentation: 京都
  • Year and Date: 2016-06-15
  • Invited
• [Presentation] 細胞内マグネシウム調節の異常とがん悪性化 (2016)
  • Author(s): 三木 裕明
  • Organizer: タイムシグナルと制御シンポジウム
  • Place of Presentation: 下田
  • Year and Date: 2016-06-11
  • Invited
• [Presentation] 細胞内マグネシウム調節とがん悪性化 (2016)
  • Author(s): 三木 裕明
  • Organizer: 第53回日本臨床分子医学会学術集会シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2016-04-15
  • Invited
• [Presentation] Redox regulation of magnesium-ion transporter MagEx/CNNM (2015)
  • Author(s): Yosuke Funato, Daisuke Yamazaki, Hiroaki Miki
  • Organizer: BMB2015
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-01
  • Invited
• [Presentation] MgイオントランスポーターCNNM/MagExの分子機能とがん悪性化 (2015)
  • Author(s): 三木 裕明
  • Organizer: 生理学研究所研究会
  • Place of Presentation: 岡崎
  • Year and Date: 2015-09-15
  • Invited
• [Presentation] マグネシウムイオン輸送のレドックス制御 (2015)
  • Author(s): 船戸 洋佑、山崎 大輔、三木 裕明
  • Organizer: 第１５回日本蛋白質科学会年会
  • Place of Presentation: 徳島
  • Year and Date: 2015-06-24
  • Invited
• [Presentation] Mg2+ efflux by CNNM4 Mediates Intestinal Magnesium Absorption and Suppresses Malignant Progression of Tumors. (2015)
  • Author(s): Miki H.
  • Organizer: Ion Channels, transporters, and small molecules as key regulators of homeostatic systems
  • Place of Presentation: Nagoya Congress Center
  • Year and Date: 2015-03-17
  • Invited