Modification of mitochondrial fission factor, DRP1 affects the biotransformation of glucose through sulfur-containing amino acid metabolism.

• Project/Area Number: 24510304
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Living organism molecular science
• Research Institution: Keio University
• Principal Investigator: YAMAMOTO Takehiro 慶應義塾大学, 医学部, 講師 (50383774)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: メチル化 / ミトコンドリア / Drp1 / Gfer / 解糖系 / メチオニン代謝 / 含硫アミノ酸 / 含硫アミノ酸代謝

Outline of Final Research Achievements

Mitochondrial dynamics (fusion vs fission) have been closely linked to cell fate and homeostasis to maintain mitochondrial functions. Recent studies showed that posttranslational modifications of several mitochondrial GTPases are involved in regulation of their shape. Here, we showed evidences that mitochondrial fission factor, DRP1 (dynamin-like protein 1) and GFER (growth factor, augmenter of live regeneration) were arginine-methylated in vitro. Furthermore, artificial inhibition of methionine cycle using modified culture medium reduced the expression level of DRP1 coincident with the suppression of glycolytic flux. On the contrary, we found that activation of glycolytic flux caused mitochondrial fission through the DRP1 induction with murine macrophage differentiation model. These results suggest that changes in mitochondrial shape through the regulation of methionine metabolism might alter the balance of glucose utilization between glycolysis and oxidative phosphorylation.

Research Products

• [Journal Article] Impacts of CD44 knockdown in cancer cells on tumor and host metabolic systems revealed by quantitative imaging mass spectrometry. (2014)
  • Author(s): Ohmura M, Hishiki T, Yamamoto T, Nakanishi T, Kubo A, Tsuchihashi K, Tamada M, Toue S, Kabe Y, Saya H and Suematsu M
  • Journal Title: Nitric Oxide Volume: pii: S1089-8603 Pages: 495-499
  • DOI: 10.1016/j.niox.2014.11.005
  • Peer Reviewed / Open Access
• [Journal Article] メチオニン代謝の変動ががんの代謝を決める~アルギニンメチル化修飾によるがん細胞の糖代謝制御 (2014)
  • Author(s): 山本雄広、高野直治、石渡恭子、末松 誠
  • Journal Title: 実験医学増刊 Volume: 32 Pages: 78-85
• [Journal Article] Reduced methylation of PFKFB3 in cancer cells shunts glucose towards the pentose phosphate pathway. (2014)
  • Author(s): Takehiro Yamamoto, Naoharu Takano, Kyoko Ishiwata, Mitsuyo Ohmura, Yoshiko Nagahata, Tomomi Matsuura, Aki Kamata, Kyoko Sakamoto, Tsuyoshi Nakanishi, Akiko Kubo, Takako Hishiki, and Makoto Suematsu.
  • Journal Title: Nature Communications Volume: 5 Issue: 1 Pages: 3480-3480
  • DOI: 10.1038/ncomms4480
  • Peer Reviewed
• [Journal Article] Energy management by enhanced glycolysis in G1-phase in human colon cancer cells in vitro and in vivo. (2013)
  • Author(s): Bao Y, Mukai K, Hishiki T, Kubo A, Ohmura M, Sugiura Y, Matsuura T, Nagahata Y, Hayakawa N, Yamamoto T, Fukuda R, Saya H, Suematsu M, Minamishima YA.
  • Journal Title: Mol Cancer Res. Volume: 11 Issue: 9 Pages: 973-985
  • DOI: 10.1158/1541-7786.mcr-12-0669-t
  • Peer Reviewed
• [Journal Article] Modulation of glucose metabolism by CD44 contributes to antioxidant status and drug resistance in cancer cells. (2012)
  • Author(s): Tamada M, Nagano O, Tateyama S, Ohmura M, Yae T, Ishimoto T, Sugihara E, Onishi N, Yamamoto T, Yanagawa H, Suematsu M, and Saya H.
  • Journal Title: Cancer Research Volume: 72 Pages: 1438-1448
  • Peer Reviewed
• [Journal Article] Carbon monoxide : Impact on remethylation and transsulfuration metabolism and its pathophysiologic implications (2012)
  • Author(s): Hishiki T, Yamamoto T, Morikawa T, Kubo A, Kajimura M, Suematsu M
  • Journal Title: Journal of molecular medicine Volume: 90 Issue: 3 Pages: 245-254
  • DOI: 10.1007/s00109-012-0875-2
  • Peer Reviewed
• [Presentation] アルギニンメチル化修飾が制御するがん細胞の代謝 (2014)
  • Author(s): 山本雄広、高野直治、石渡恭子、末松誠
  • Organizer: 第37回日本分子生物学会
  • Place of Presentation: 横浜市
  • Year and Date: 2014-11-26
• [Presentation] 解糖系酵素PFKFB3のメチル化修飾によるがん細胞の糖代謝制御 (2014)
  • Author(s): 山本雄広、高野直治、石渡恭子、大村光代、長畑善子、松浦友美、久保亜希子、菱木貴子、末松誠
  • Organizer: 第87回日本生化学会
  • Place of Presentation: 京都市
  • Year and Date: 2014-10-16
• [Presentation] ミトコンドリアの形態変化による細胞内エネルギー代謝調節機構の解明 (2014)
  • Author(s): 山本雄広
  • Organizer: 第3回マトリョーシカ型生物学研究会
  • Place of Presentation: 神戸市
  • Year and Date: 2014-07-11 – 2014-07-13
• [Presentation] 解糖系酵素PFKFB3のメチル化制御はがん細胞の酸化ストレス耐性獲得に重要である (2013)
  • Author(s): 山本雄広、石渡恭子、高野直治、大村光代、菱木貴子、長畑善子、末松 誠
  • Organizer: 第86回 日本生化学会本大会
  • Place of Presentation: パシフィコ横浜
• [Presentation] アルギニンメチル化酵素PRMT1の細胞内局在を反映した糖代謝酵素の核内メチル化機構 (2013)
  • Author(s): 山本雄広、石渡恭子、高野直治、大村光代、菱木貴子、長畑善子、末松 誠
  • Organizer: 第36回 日本分子生物学会本大会
  • Place of Presentation: 神戸ポートアイランド
• [Presentation] 一酸化炭素（CO）を介したアルギニンメチル化制御による糖代謝リモデリング機構の解明 (2012)
  • Author(s): 山本雄広、石渡恭子、高野直治、菱木貴子、長畑善子、末松 誠
  • Organizer: 第85回 日本生化学会大会
  • Place of Presentation: 福岡国際会議場、福岡市
• [Presentation] Carbon monoxide regulates directional biotransformation of glucose via protein arginine methylation (2012)
  • Author(s): Takehiro Yamamoto, Kyoko Ishiwata, Naoharu Takano, Makoto Suematsu
  • Organizer: 第33回 内藤コンファレンス酸素生物学：酸素濃度に対する生物応答とその制御破綻による疾患」
  • Place of Presentation: ガトーキングダム、札幌市
• [Book] 酸化ストレスの医学 (2014)
  • Author(s): 末松 誠、山本雄広、梶村眞弓
  • Total Pages: 8
  • Publisher: 診断と治療社
• [Remarks] 慶應義塾大学医学部医化学教室ホームページ
  • URL: http://www.gasbiology.com/