Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
Brain Res. 2012 Mar 29;1446:1-11. doi: 10.1016/j.brainres.2012.01.046. Epub 2012 Jan 28.
Cellular stress or injury can result in mitochondrial dysfunction, which has been linked to many chronic neurological disorders including amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD). Stressed and dysfunctional mitochondria exhibit an increase in large conductance mitochondrial membrane currents and a decrease in bioenergetic efficiency. Inefficient energy production puts cells, and particularly neurons, at risk of death when energy demands exceed cellular energy production. Here we show that the candidate ALS drug dexpramipexole (DEX; KNS-760704; ((6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine) and cyclosporine A (CSA) inhibited increases in ion conductance in whole rat brain-derived mitochondria induced by calcium or treatment with a proteasome inhibitor, although only CSA inhibited calcium-induced permeability transition in liver-derived mitochondria. In several cell lines, including cortical neurons in culture, DEX significantly decreased oxygen consumption while maintaining or increasing production of adenosine triphosphate (ATP). DEX also normalized the metabolic profile of injured cells and was protective against the cytotoxic effects of proteasome inhibition. These data indicate that DEX increases the efficiency of oxidative phosphorylation, possibly by inhibition of a CSA-sensitive mitochondrial conductance.
细胞应激或损伤会导致线粒体功能障碍，这与许多慢性神经紊乱有关，包括肌萎缩侧索硬化症（ALS）和帕金森病（PD）。应激和功能失调的线粒体表现出大电导线粒体膜电流增加和生物能量效率降低。当能量需求超过细胞能量产生时，低效的能量产生会使细胞，特别是神经元面临死亡的风险。在这里，我们表明候选 ALS 药物 dexpramipexole（DEX；KNS-760704；（（6R）-4,5,6,7-四氢-N6-丙基-2,6-苯并噻唑二胺）和环孢菌素 A（CSA）抑制了钙诱导的或用蛋白酶体抑制剂处理的全大鼠脑衍生线粒体中离子电导的增加，尽管只有 CSA 抑制了肝衍生线粒体中的钙诱导的通透性转变。在包括培养中的皮质神经元在内的几种细胞系中，DEX 显著降低了耗氧量，同时维持或增加了三磷酸腺苷（ATP）的产生。DEX 还使受损细胞的代谢谱正常化，并能抵抗蛋白酶体抑制的细胞毒性作用。这些数据表明 DEX 通过抑制 CSA 敏感的线粒体电导来提高氧化磷酸化的效率。
