Microtubule Disorganization Affects the Mitochondrial Permeability Transition Pore in Cardiac Myocytes
Microtubule Disorganization Affects the Mitochondrial Permeability Transition Pore in Cardiac Myocytes
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DOI：
10.1253/circj.cj-13-1298
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发表时间：
2014-05-01
影响因子：
3.3
通讯作者：
Hayashi, Hideharu
中科院分区：
文献类型：
--
作者：
Kumazawa, Azumi;Katoh, Hideki;Hayashi, Hideharu
背景：微管（MT）紊乱与心脏疾病有关。为了阐明MT网络的紊乱使心功能恶化的机制，研究了心肌细胞中MT网络紊乱与线粒体通透性转换孔（mPTP）之间的关系。MT稳定化的影响（通过紫杉醇）和MT破坏在透化的Sprague-Dawley大鼠肌细胞中测量（通过诺考达唑）对线粒体膜电位（Δ psi m）和mPTP开放的影响。紫杉醇和诺考达唑都使Δ psi m去极化并开放mPTP。当分离的线粒体暴露于紫杉醇或诺考达唑时，Δ psi m没有变化。紫杉醇或诺考达唑对Δ psi m去极化和mPTP的作用可被环孢素A抑制。用0 Ca +BAPTA处理心肌细胞或用毒胡萝卜素抑制肌浆网（SR）Ca 2+摄取可阻止紫杉醇对mPTP的作用，但不能阻止诺考达唑的作用。Ru 360对线粒体Ca 2+单向转运体的抑制并不改变紫杉醇对mPTP的作用。紫杉醇减少线粒体融合蛋白，mitofusin-2的表达，并诱导线粒体fragmentation.Conclusions：破坏的MT网络诺考达唑可能会破坏MT-线粒体连接，改变线粒体功能。紫杉醇对MT的破坏可以通过线粒体外膜复合物和Ca 2+敏感的信号通路调节mPTP，该信号通路还与线粒体融合蛋白mitofusin-2相互作用。
Background: Microtubule (MT) disorganization is related to cardiac disorders. To elucidate the mechanism by which disorganization of the MT network deteriorates cardiac function, the relationship between MT disorganization and mitochondrial permeability transition pore (mPTP) in cardiac myocytes was investigated.Methods and Results: The effects of MT stabilization (by paclitaxel) and MT disruption (by nocodazole) on mitochondrial membrane potential (Delta psi m) and the opening of mPTP were measured in permeabilized Sprague-Dawley rat myocytes. Both paclitaxel and nocodazole depolarized Delta psi m and opened mPTP. When isolated mitochondria were exposed to paclitaxel or nocodazole, there were no changes in Delta psi m. The effects of paclitaxel or nocodazole on Delta psi m depolarization and mPTP were inhibited by cyclosporin A. Treatment of myocytes with 0Ca+BAPTA or inhibition of sarcoplasmic reticulum (SR) Ca2+ uptake by thapsigargin prevented the effect of paclitaxel on mPTP, but not that of nocodazole. Inhibition of the mitochondrial Ca2+ uniporter by Ru360 did not alter the effect of paclitaxel on mPTP. Paclitaxel reduced the expression of the mitochondrial fusion protein, mitofusin-2, and induced mitochondrial fragmentation.Conclusions: Disruption of the MT network by nocodazole might destroy the MT-mitochondria connection and alter mitochondrial function. MT disorganization by paclitaxel could regulate mPTP through the outer mitochondrial membrane complex and the Ca2+-sensitive signaling pathway, which also interacts with the mitochondrial fusion protein, mitofusin-2.