Elucidation of mechanism for coupling factor 6-induced accelerated aging and identification of its inhibitory protein

• Project/Area Number: 15K09151
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Hirosaki University
• Principal Investigator: OSANAI TOMOHIRO 弘前大学, 保健学研究科, 教授 (00169278)
• Co-Investigator(Kenkyū-buntansha): 奥村 謙 弘前大学, 医学研究科, 客員研究員 (20185549)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: coupling factor 6 / aging / autophagy / telomere / epigenetics / genomic instability / inhibitory protein 1 / acidosis / lamina / inhibitory factor 1

Outline of Final Research Achievements

Coupling factor 6 (CF6) converts the rotation of ecto-F1Fo complex from a clockwise mode of proton export to a counter-clockwise mode of proton import. Inhibitory peptide 1 (IF1) is a unidirectional inhibitor of ATP hydrolysis. TG cells displayed the decrease in lamin and emerin and the increase in H3K4me3 and H4K20me3. LC3 II and lysosome were stained weakly in the peripheral cytoplasm in TG cells. LC3 II and P62 were increased and Atg7 was decreased in TG cells. Telomere length was shorter in TG cells. Overexpression of IF1 rescued TG cells from all aging hallmarks. IF1 suppressed CF6-induced expression of aging hallmarks, and may function as an anti-aging molecule.

Research Products

• [Journal Article] Enhanced transient receptor potential channel-mediated Ca2+ influx in the cells with phospholipase C-delta1 overexpression: its possible role in coronary artery spasm. (2017)
  • Author(s): Murakami K, Osanai T, Tanaka M, Nishizaki K, Kinjo T, Tanno T, Ishida Y, Suzuki A, Endo T, Tomita H, Okumura K.
  • Journal Title: Fundam Clin Pharmacol. Volume: 31 Pages: 383-391
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Nutritional regulation of coupling factor 6, a novel vasoactive and proatherogenic peptide. (2017)
  • Author(s): Osanai T, Mikami K, Kitajima M, Urushizaka M, Kawasaki K, Tomisawa T, Itaki C, Noto Y, Magota K, Tomita H.
  • Journal Title: Nutrition Volume: 37 Pages: 74-78
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Mitochondrial Inhibitory Factor Protein 1 Functions as an Endogenous Inhibitor for Coupling Factor 6. (2016)
  • Author(s): Kawai M, Osanai T, Tanaka M, Magota K, Tomita H, Okumura K.
  • Journal Title: J Cell Biochem Volume: 117 Pages: 1680-1687
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Modified sympathetic nerve regulation in AKAP5-null mice. (2016)
  • Author(s): Han C, Tomita H, Ohba T, Nishizaki K, Ogata Y, Matsuzaki Y, Sawamura D, Yanagisawa T, Osanai T, Imaizumi T, Matsubara A, Adachi T, Ono K, Okumura K, Murakami M
  • Journal Title: Biochem Biophys Res Commun Volume: 469 Pages: 897-902
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Olmesartan inhibits cardiac hypertrophy in mice overexpressing renin independently of blood pressure: its beneficial effects on ACE2/Ang(1-7)/Mas axis and NADPH oxidase expression. (2016)
  • Author(s): Tanno T, Tomita H, Narita I, Kinjo T, Nishizaki K, Ichikawa H, Kimura Y, Tanaka M, Osanai T, Okumura K.
  • Journal Title: J Cardiovasc Pharmacol. Volume: 67 Pages: 503-509
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Quality of Life in Physical and Psychological Health and Social Environment at Posthospitalization Period in Patients with Stroke. (2016)
  • Author(s): Karube N, Sasaki A, Hondoh F, Odagiri C, Hagii J, Seino S, Yasujima M, Osanai T.
  • Journal Title: J Stroke Cerebrovasc Dis Volume: 25 Pages: 2482-2487
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Plasma Soluble Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 as a Novel Prognostic Biomarker in Patients With ST-Segment Elevation Acute Myocardial Infarction. (2015)
  • Author(s): Higuma T, Abe N, Tateyama S, Endo T, Shibutani S, Yokoyama H, Hanada K, Yamada M, Tomita H, Hanada H, Osanai T, Kume N, Okumura K.
  • Journal Title: Circ J Volume: 79 Pages: 641-648
  • NAID: 130004927094
  • Peer Reviewed
• [Journal Article] Deeply reinverted T wave at 14 days after the onset of first anterior acute myocardial infarction predicts improved left ventricular function at 6 months. (2015)
  • Author(s): Yokoyama H, Tomita H, Nishizaki F, Hanada K, Shibutani S, Yamada M, Abe N, Higuma T, Osanai T, Okumura K
  • Journal Title: Clin Cardiol Volume: 38 Pages: 157-163
  • Peer Reviewed
• [Journal Article] Impact of Sex Difference on Severity and Functional Outcome in Patients with Cardioembolic Stroke (2015)
  • Author(s): Tomita H, Hagii J, Metoki N, Saito S, Shiroto H, Hitomi H, Kamada T, Seino S, Takahashi K, Baba Y, Sasaki S, Uchizawa T, Iwata M, Matsumoto S, Shoji Y, Tanno T, Osanai T, Yasujima M, Okumura K.
  • Journal Title: J Stroke Cerebrovasc Dis Volume: 24 Pages: 2613-2618
  • Peer Reviewed
• [Journal Article] Enhanced p122RhoGAP/DLC-1 Expression Can Be a Cause of Coronary Spasm (2015)
  • Author(s): Kinjo T, Tanaka M, Osanai T, Shibutani S, Narita I, Tanno T, Nishizaki K, Ichikawa H, Kimura Y, Ishida Y, Yokota T, Shimada M, Homma Y, Tomita H, Okumura K
  • Journal Title: PLoS One Volume: 10
  • Peer Reviewed
• [Presentation] ATPase inhibitory factor 1 は老化促進ペプチドcoupling factor 6の内因性阻害物質であり、アンチエイジング作用を発揮する (2017)
  • Author(s): 長内智宏
  • Organizer: 第40回日本高血圧学会総会
• [Presentation] Coupling factor 6 accelerates aging by synchronizing primary aging hallmarks such as telomere attrition and a blocking effect of ATPase inhibitory factor 1 (2016)
  • Author(s): Tomohiro Osanai, Kei Izumiyama, Makoto Tanaka, Hirofumi Tomita, Akihiro Kobayashi, Ken Okumura
  • Organizer: AHA Scientific Sessions 2016
  • Place of Presentation: New Orleans, Louisiana, USA
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] Coupling factor 6は核内酸性化によるautophagy障害を介して老化を促進させ、IF1はその作用に拮抗する作用を有する (2016)
  • Author(s): 長内智宏、樋熊拓未、富田泰史
  • Organizer: 第39回日本高血圧学会総会
  • Place of Presentation: 仙台国際センター(宮城県仙台市）
  • Year and Date: 2016-09-30
• [Presentation] 食塩はcoupling factor 6と同様に細胞内酸性化を介して老化スイッチをオンする (2015)
  • Author(s): 長内智宏、泉山圭、富田泰史、奥村謙
  • Organizer: 第38回日本高血圧学会
  • Place of Presentation: ひめぎんホール（愛媛県松山市）
  • Year and Date: 2015-10-09
• [Presentation] Coupling factor 6 is an endogenous stimulator for atherosclerosis through salt-sensitive hypertension and type 2 diabetes (2015)
  • Author(s): Tomohiro Osanai, Makoto Tanaka, Kei Izumiyama, Hirofumi Tomita, Ken Okumura
  • Organizer: 17TH International Congress on Atherosclerosis
  • Place of Presentation: Amsterdam, Netherland
  • Year and Date: 2015-05-23
  • Int'l Joint Research