Integrated analyses of mitochondria degradation system as a novel therapeutic target of heart failure

• Project/Area Number: 15H04822
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Osaka University
• Principal Investigator: OTSU Kinya 大阪大学, 先導的学際研究機構, 招へい教授 (20294051)
• Co-Investigator(Kenkyū-buntansha): 彦惣 俊吾 大阪大学, 医学系研究科, 寄附講座准教授 (30423164) ; 山口 修 大阪大学, 医学系研究科, 准教授 (90467580)
• Research Collaborator: MURAKAWA Tomokazu
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000); Fiscal Year 2017: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2016: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000); Fiscal Year 2015: ¥8,450,000 (Direct Cost: ¥6,500,000、Indirect Cost: ¥1,950,000)
• Keywords: ミトコンドリア / 心不全 / オートファジー

Outline of Final Research Achievements

The accumulation of damaged mitochondria is involved in the pathogenesis and progression of heart failure. However, the precise role and molecular mechanism is not elucidated. We identified BCL2L13 as a novel mitophagy receptor on outer mitochondrial membrane. BCL2L13 binds to LC3 through the WXXI motif and induces both mitochondrial fragmentation and mitophagy not only in HEK293 cells but in isolated rat neonatal cardiomyocytes. Furthermore, we generated and analyzed cardiac-specific deficient mice of BCL2L13, TSC2 and FKBP8, and we revealed cardio-protective role of TSC2 and FKBP8.

Research Products

• [Int'l Joint Research] King's College London(英国)
• [Int'l Joint Research] King's College London(英国)
• [Int'l Joint Research] King's College London(英国)
• [Journal Article] FKBP8 protects the heart from hemodynamic stress by preventing the accumulation of misfolded proteins and endoplasmic reticulum-associated apoptosis in mice. (2018)
  • Author(s): Misaka T, Murakawa T, Nishida K, Omori Y, Taneike M, Omiya S, Molenaar C, Uno Y, Yamaguchi O, Takeda J, Shah AM, Otsu K.
  • Journal Title: J Mol Cell Cardiol. Volume: 114 Pages: 93-104
  • DOI: 10.1016/j.yjmcc.2017.11.004
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mitochondrial DNA as an inflammatory mediator in cardiovascular diseases. (2018)
  • Author(s): Nakayama H, Otsu K.
  • Journal Title: Biochem J. Volume: 475 Issue: 5 Pages: 839-852
  • DOI: 10.1042/bcj20170714
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Fibroblast-Specific Genetic Manipulation of p38 Mitogen-Activated Protein Kinase In Vivo Reveals Its Central Regulatory Role in Fibrosis. (2017)
  • Author(s): Molkentin JD, Bugg D, Ghearing N, Dorn LE, Kim P, Sargent MA, Gunaje J, Otsu K, Davis J.
  • Journal Title: Circulation. 2017 Aug 8;136(6):549-561 Volume: 136 Issue: 6 Pages: 549-561
  • DOI: 10.1161/circulationaha.116.026238
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Sterile Inflammation and Degradation Systems in Heart Failure (2017)
  • Author(s): Nishida K, Otsu K.
  • Journal Title: Circulation Journal Volume: 81 Issue: 5 Pages: 622-628
  • DOI: 10.1253/circj.CJ-17-0261
  • NAID: 130005612036
  • ISSN: 1346-9843, 1347-4820
  • Open Access / Int'l Joint Research
• [Journal Article] Inflammation and metabolic cardiomyopathy. (2017)
  • Author(s): Nishida K, Otsu K.
  • Journal Title: Cardiovasc Res. Volume: 113 Issue: 4 Pages: 389-398
  • DOI: 10.1093/cvr/cvx012
  • Int'l Joint Research
• [Journal Article] Toll-like receptor 9 prevents cardiac rupture after myocardial infarction in mice independently of inflammation. (2016)
  • Author(s): Omiya S, Omori Y, Taneike M, Protti A, Yamaguchi O, Akira S, Shah AM, Nishida K, Otsu K.
  • Journal Title: Am J Physiol Heart Circ Physiol. Volume: 311 Issue: 6 Pages: H1485-H1497
  • DOI: 10.1152/ajpheart.00481.2016
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] mTOR Hyperactivation by Ablation of Tuberous Sclerosis Complex 2 in the Mouse Heart Induces Cardiac Dysfunction with the Increased Number of Small Mitochondria Mediated through the Down-Regulation of Autophagy. (2016)
  • Author(s): Taneike M, Nishida K, Omiya S, Zarrinpashneh E, Misaka T, Kitazume-Taneike R, Austin R, Takaoka M, Yamaguchi O, Gambello MJ, Shah AM, Otsu K.
  • Journal Title: PLoS One Volume: 11 Issue: 3 Pages: e0152628-e0152628
  • DOI: 10.1371/journal.pone.0152628
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] BCL2L13 is a mammalian homolog of the yeast mitophagy receptor Atg32. (2015)
  • Author(s): Otsu K, Murakawa T, Yamaguchi O.
  • Journal Title: Autophagy Volume: 11 Issue: 10 Pages: 1932-3
  • DOI: 10.1080/15548627.2015.1084459
  • Int'l Joint Research
• [Journal Article] Bcl-2-like protein 13 is a mammalian Atg32 homologue that mediates mitophagy and mitochondrial fragmentation. (2015)
  • Author(s): Murakawa T, Yamaguchi O, Hashimoto A, Hikoso S, Takeda T, Oka T, Yasui H, Ueda H, Akazawa Y, Nakayama H, Taneike M, Misaka T, Omiya S, Shah AM, Yamamoto A, Nishida K, Ohsumi Y, Okamoto K, Sakata Y, Otsu K.
  • Journal Title: Nat Commun. Volume: 6 Issue: 1 Pages: 7527-7527
  • DOI: 10.1038/ncomms8527
  • Peer Reviewed / Open Access / Int'l Joint Research