Roles of mitochondrial connexin43 in the occurrence of arrhythmias during myocardial ischemia

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K07298
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 48020:Physiology-related
• Research Institution: Tohoku University
• Principal Investigator: Miura Masahito 東北大学, 医学系研究科, 教授 (30302110)
• Co-Investigator(Kenkyū-buntansha): 佐藤 遥 東北大学, 医学系研究科, 助教 (90803883)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: 不整脈 / コネキシン43 / ミトコンドリア

Outline of Final Research Achievements

Connexin43 (Cx43) exits as hemichannels in the inner mitochondrial membrane. We examined how mitochondrial Cx43 and mitochondrial KATP channels affect the occurrence of triggered arrhythmias. Cardiac-specific Cx43-deficient (cCx43-/-) mice were generated. In cCx43-/- mice, arrhythmias were induced by electrical stimulation at lower [Ca2+]o, and Ca2+ spark frequency, the slope of DCF fluorescence intensity, MitoSoxRed fluorescence, and rhod-2 fluorescence were increased. TMRM fluorescence was decreased in cCx43-/- mice. These changes were suppressed by diazoxide. In cCx43-/- mice, SS-31 and N-acetyl-L-cysteine increased the [Ca2+]o, at which arrhythmias were induced. These results suggest that Cx43 deficiency activates Ca2+ leak from the SR, probably due to an increase in mitochondrial Ca2+ and an increase in ROS production, thereby causing triggered arrhythmias, and that Cx43 hemichannel deficiency may be compensated by activation of mitochondrial KATP channels in mouse hearts.

Free Research Field

生理学

Academic Significance and Societal Importance of the Research Achievements

不全心や虚血心などにおける細胞内のカルシウム負荷や筋小胞体カルシウム放出チャネルのカルシウム感受性の変化は、カルシウム・スパーク頻度を変化させる。このようなスパーク頻度の変化が、催不整脈性に関与することはよく知られており、催不整脈性における筋小胞体の役割は確立している。一方で、ミトコンドリアの催不整脈性への関与に関しては、ミトコンドリア膜透過性遷移孔の一過性開口やミトコンドリア内カルシウム濃度の上昇がミトコンドリア内ROS産生を増加させ、不整脈を誘発することなどが報告されているものの、依然として詳細は不明である。本研究は、Cx43を標的とした全く新しい発想からの不整脈治療に繋がる可能性がある。