Roles of mitochondrial iron homeostasis in development and progression of heart failure

• Project/Area Number: 17K16016
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Cardiovascular medicine
• Research Institution: Sapporo Medical University
• Principal Investigator: SATO TATSUYA 札幌医科大学, 医学部, 助教 (40592473)
• Research Collaborator: Kikuchi Tatsuya
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: ミトコンドリア / 鉄代謝 / 心不全 / 分子心臓学 / 鉄

Outline of Final Research Achievements

Impaired mitochondrial iron homeostasis is known to lead to development of heart failure through increased oxidative stress. However, the details are still unclear because the way to evaluate distribution of cardiac mitochondrial iron has not been established. In this study, we examined how cardiac mitochondrial iron homeostasis is impaired in the models of heart failure by energy dispersive X-ray spectroscopy (EDS) using an aberration-corrected scanning electron microscope. Mice model of doxorubicin-induced cardiomyopathy showed increased mitochondrial iron content measured by biochemical Ferrozin assay. However, mapping of mitochondrial iron by EDS resulted in a rather small iron signal on the mitochondrial cristae and there was no iron accumulation in the mitochondria. The findings suggest that free iron, which catalyzes production of hydroxyl radicals, is increased and mitochondria-specific iron chelation is promising therapeutic target in doxorubicin-induced cardiomyopathy.

Academic Significance and Societal Importance of the Research Achievements

本研究により、心筋ミトコンドリアにおける鉄恒常性の破綻を、収差補正走査型電子顕微鏡Titanを用いたエネルギー分散X線分光法 (EDS) により詳細に解析できる可能性が示唆された。これは、患者から得られた心筋生検標本に対しても応用が可能であることを意味する。今後は解析対象を患者心筋生検標本に拡大し、ミトコンドリア鉄恒常性の破綻が治療標的となりうる疾患像を明らかにすることで臨床への応用を目指し、更に研究を進めていく。

Research Products

• [Journal Article] Canagliflozin, a sodium-glucose cotransporter-2 inhibitor, normalizes renal susceptibility to type?1 cardiorenal syndrome through reduction of renal oxidative stress in diabetic rats (2019)
  • Author(s): Kimura Yukishige、Kuno Atsushi、Tanno Masaya、Sato Tatsuya、Ohno Kouhei、Shibata Satoru、Nakata Kei、Sugawara Hirohito、Abe Koki、Igaki Yusuke、Yano Toshiyuki、Miki Takayuki、Miura Tetsuji
  • Journal Title: Journal of Diabetes Investigation Volume: in Press Issue: 4 Pages: 933-946
  • DOI: 10.1111/jdi.13009
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Empagliflozin, an SGLT2 Inhibitor, Reduced the Mortality Rate after Acute Myocardial Infarction with Modification of Cardiac Metabolomes and Antioxidants in Diabetic Rats (2018)
  • Author(s): Oshima Hiroto、Miki Takayuki、Kuno Atsushi、Mizuno Masashi、Sato Tatsuya、Tanno Masaya、Yano Toshiyuki、Nakata Kei、Kimura Yukishige、Abe Koki、Ohwada Wataru、Miura Tetsuji
  • Journal Title: Journal of Pharmacology and Experimental Therapeutics Volume: 368 Issue: 3 Pages: 524-534
  • DOI: 10.1124/jpet.118.253666
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] mRNA-binding protein tristetraprolin is essential for cardiac response to iron deficiency by regulating mitochondrial function (2018)
  • Author(s): Sato Tatsuya、Chang Hsiang-Chun、Bayeva Marina、Shapiro Jason S.、Ramos-Alonso Lucia、Kouzu Hidemichi、Jiang Xinghang、Liu Ting、Yar Sumeyye、Sawicki Konrad T.、Chen Chunlei、Mart?nez-Pastor Mar?a Teresa、Stumpo Deborah J.、Schumacker Paul T.、Blackshear Perry J.、Ben-Sahra Issam、Puig Sergi、Ardehali Hossein
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 115 Issue: 27
  • DOI: 10.1073/pnas.1804701115
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Empagliflozin normalizes the size and number of mitochondria and prevents reduction in mitochondrial size after myocardial infarction in diabetic hearts. (2018)
  • Author(s): Mizuno M, Kuno A, Yano T, Miki T, Oshima H, Sato T, Nakata K, Kimura Y, Tanno M, Miura T
  • Journal Title: Physiological Reports Volume: 6 Issue: 12 Pages: e13741-e13741
  • DOI: 10.14814/phy2.13741
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Infarct size-liming effect of continuous erythropoietin receptor activator in chronic kidney disease is eliminated by use of its excessive dose. (2019)
  • Author(s): Sato T, Yano T, Nishizawa K, Kimura Y, Miki T, Tanno M, Kuno A, Hirata M, Kawasaki R, Miura T
  • Organizer: 第83回日本循環器学会年次学術集会
• [Presentation] mRNA Binding Protein Tristetraprolin is Required for Cardiac Protection Against Iron Deficiency Through Regulating Production of Mitochondrial Electron Transport Chain Components (2018)
  • Author(s): Sato T, Chang HC, Bayeva M, Shapiro JS, Ramos-Alonso L, Kouzu H, Jiang X, Liu T, Yar S, Sawicki KT, Chen C, Stumpo DJ, Schumacker P, Blackshear PJ, Ben-Sahra I, Puig S, Ardehali H.
  • Organizer: American Heart Association Annual Meeting 2018
  • Int'l Joint Research
• [Presentation] 鉄欠乏に対するミトコンドリアの新規適応機構 (2018)
  • Author(s): Sato T, Tanno M, Miki T, Yano T, Chang HC, Ardehali H, Miura T.
  • Organizer: 第18回日本抗加齢学会総会
  • Invited
• [Presentation] Tristetraprolin prevents iron deficiency-induced mitochondrial ROS production by optimizing expression of UQCRFS1 iron-containing mitochondrial protein in parallel with iron availability. (2018)
  • Author(s): Sato T, Tanno M, Miki T, Yano T, Chang HC, Ardehali H, Miura T.
  • Organizer: 第1回日本循環器学会基礎研究フォーラム