Regulation of Mitochondrial Function in Cardiac Myocytes : Kinetics of the Opening of mPTP and it's Physiological Roles

心肌细胞线粒体功能的调节：mPTP 开放的动力学及其生理作用

• 批准号: 13670703
• 负责人: KATOH Hideki
• 金额: $ 2.11万
• 依托单位: HAMAMATSU UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670703/
• 关键词: mitochondria; confocal microscopy; calcium; diazoxide; permeability transition pore; saponin; cyclosporine A; membrane potential; calcein

Mitochondrial permeability transition pore (mPTP) has been considered to play important roles not only as a mechanism of ischemia reperfusion injury, but also for the maintenance of cellular function under physiological condition. In this project we aimed to study (1) the kinetics of the opening of mPTP and it's regulation by mitochondrial Ca^<2+> concentration ([Ca^<2+>]m) and mitochondrial membrane potential (ΔΨ_m), (2) the effects of the opening of mPTP on [Ca^<2+>]_m and cytosolic Ca^<2+> concentration ([Ca^<2+>]_c) and (3) the interaction between mitochondria and sarcoplasmic reticulum (SR) by using confocal microscopy.We have developed methods to monitor [Ca^<2+>]_m and the opening of mPTP in intact and saponin permeabilized cardiac myocytes. By using these methods, we have found that mitochondrial ATP sensitive potassium channel opener, Diazoxide opened mPTP and released Ca^<2+> from mitochondrial matrix to cytosol. This increase in [Ca^<2+>]_c then increased Ca^<2+> transients and Ca^<2+> sparks. Measurement of [Ca^<2+>]_m revealed that Diazoxide reduced [Ca^<2+>]_m. Finally we have investigated the relation between [Ca^<2+>]_m and ΔΨ_m and found that in the pathophysiological condition, where ΔΨ_m was dissipated, opening of mPTP and mitochondrial Na^+/Ca^<2+> exchange were important for the regulation of [Ca^<2+>]_m.

线粒体通透性转换孔(MPTP)不仅被认为是缺血再灌注损伤的重要机制，而且在生理条件下对细胞功能的维持也起着重要作用。本课题旨在研究(1)线粒体钙离子浓度([Ca^&lt；2+&gt；]m)和线粒体膜电位(ΔΨ_m)对线粒体钙离子浓度([Ca^&lt；2+&gt；]m)和线粒体膜电位([Ca^&lt；2+&gt；]m)的影响；(2)MPTP开放对细胞内钙离子浓度([Ca^&lt；2+&gt；)C)和(3)线粒体与肌浆网(SR)之间的相互作用。我们建立了监测完整和皂苷通透性心肌细胞[Ca~(2+)]_m和MPTP开放的方法。通过这些方法，我们发现线粒体ATP敏感性钾通道开放剂二氮嗪开放MPTP，并将线粒体基质中的Ca~(2+)释放到胞浆中。这种[Ca^&lt；2+>]_c的增加增加了Ca^&lt；2+&gt；的瞬变和Ca^&lt；2+&gt；的火花。[Ca^&lt；2+&gt；]_m的测定表明，二氮嗪使[Ca^&lt；2+&gt；]_m降低。最后，我们研究了[Ca^&lt；2+&gt；]_m与ΔΨ_m的关系，发现在ΔΨ_m耗散的病理生理条件下，mTP开放和线粒体Na+/Ca^&lt；2+&gt；交换对[Ca^&lt；2+&gt；]_m的调节起重要作用。

项目成果

Yaguchi Y et al.: "Protective effects of hydrogen peroxide against ischemia/reperfusion injury in perfused rat hearts."Circulation Journal.. 67. 253-258 (2003)

Yaguchi Y 等人：“过氧化氢对灌注大鼠心脏缺血/再灌注损伤的保护作用。”循环杂志.. 67. 253-258 (2003)

Mark T Ziolo et al.: "Expression of inducible nitric oxide synthase depresses beta-adrenergic-stimulated calcium release from the sarcoplasmic reticulum in intact ventricular myocytes."Circulation. 104. 2961-2966 (2001)

Mark T Ziolo 等人：“诱导型一氧化氮合酶的表达会抑制完整心室肌细胞中肌浆网中 β-肾上腺素刺激的钙释放。”循环。

Satoru Ito et al.: "Possible involvement of Rho kinase in Ca2+ sensitization and mobilization by MCh in tracheal smooth muscle"Am J Physiology Lung Cell Mol Physiol.. 280. L1281-L1224 (2001)

Satoru Ito 等：“气管平滑肌中 Rho 激酶可能参与 MCh 的 Ca2 敏化和动员”Am J Physiology Lung Cell Mol Physiol.. 280. L1281-L1224 (2001)

加藤 秀樹 他: "ミトコンドリアATP感受性K^+チャネル開口薬diazoxideがCa^<2+> transientに及ぼす効果の検討"心筋の構造と代謝. 23. 195-200 (2001)

Hideki Kato 等人：“线粒体 ATP 敏感 K^+ 通道开放剂二氮嗪对 Ca^2+ 瞬变的影响的检查”《心肌结构与代谢》23. 195-200 (2001)。

Hideki Katoh et al.: "Diazoxide opens the mitochondrial permeability transition pore and alters Ca^<2+> transients in rat ventricular myocytes"Circulation. 105. 2666-2671 (2002)

Hideki Katoh 等人：“二氮嗪打开线粒体通透性转换孔并改变大鼠心室肌细胞中的 Ca^2 瞬变”循环。