Kumazawa Azumi, Katoh Hideki, Nonaka Daishi, Watanabe Tomoyuki, Saotome Masao, Urushida Tsuyoshi, Satoh Hiroshi, Hayashi Hideharu
Division of Cardiology, Internal Medicine III, Hamamatsu University School of Medicine.
Circ J. 2014;78(5):1206-15. doi: 10.1253/circj.cj-13-1298. Epub 2014 Mar 10.
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.
The effects of MT stabilization (by paclitaxel) and MT disruption (by nocodazole) on mitochondrial membrane potential (ΔΨm) and the opening of mPTP were measured in permeabilized Sprague-Dawley rat myocytes. Both paclitaxel and nocodazole depolarized ΔΨm and opened mPTP. When isolated mitochondria were exposed to paclitaxel or nocodazole, there were no changes in ΔΨm. The effects of paclitaxel or nocodazole on ΔΨm depolarization and mPTP were inhibited by cyclosporin A. Treatment of myocytes with 0Ca+BAPTA or inhibition of sarcoplasmic reticulum (SR) Ca(2+) uptake by thapsigargin prevented the effect of paclitaxel on mPTP, but not that of nocodazole. Inhibition of the mitochondrial Ca(2+) 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.
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 Ca(2+)-sensitive signaling pathway, which also interacts with the mitochondrial fusion protein, mitofusin-2.
微管（MT）紊乱与心脏疾病相关。为阐明MT网络紊乱使心脏功能恶化的机制，研究了心肌细胞中MT紊乱与线粒体通透性转换孔（mPTP）之间的关系。
在透化的Sprague-Dawley大鼠心肌细胞中测量MT稳定（通过紫杉醇）和MT破坏（通过诺考达唑）对线粒体膜电位（ΔΨm）和mPTP开放的影响。紫杉醇和诺考达唑均使ΔΨm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，ΔΨm没有变化。环孢素A抑制了紫杉醇或诺考达唑对ΔΨm去极化和mPTP的影响。用0Ca+BAPTA处理心肌细胞或用毒胡萝卜素抑制肌浆网（SR）Ca(2+)摄取可防止紫杉醇对mPTP的作用，但不能防止诺考达唑的作用。Ru360抑制线粒体Ca(2+)单向转运体不会改变紫杉醇对mPTP的作用。紫杉醇降低了线粒体融合蛋白线粒体融合蛋白2的表达并诱导线粒体碎片化。
诺考达唑破坏MT网络可能会破坏MT-线粒体连接并改变线粒体功能。紫杉醇导致的MT紊乱可通过线粒体外膜复合物和Ca(2+)敏感信号通路调节mPTP，该信号通路还与线粒体融合蛋白线粒体融合蛋白2相互作用。
