Morota Saori, Hansson Magnus J, Ishii Nagao, Kudo Yoshihisa, Elmér Eskil, Uchino Hiroyuki
Department of Anesthesiology, Tokyo Medical University Hachioji Medical Center, Tatemachi, Hachioji, Japan.
J Neurochem. 2007 Dec;103(5):2066-76. doi: 10.1111/j.1471-4159.2007.04912.x. Epub 2007 Sep 13.
The mitochondrial permeability transition (mPT) is a potential pathogenic mechanism in neurodegeneration. Varying sensitivity to calcium-induced mPT has been demonstrated for regions within the CNS possibly correlating with vulnerability following insults. The spinal cord is selectively vulnerable in e.g. amyotrophic lateral sclerosis and increased mPT sensitivity of mitochondria derived from the spinal cord has previously been demonstrated. In this study, we introduce whole-body hypothermia prior to removal of CNS tissue to minimize the effects of differential tissue extraction prior to isolation of spinal cord and cortical brain mitochondria. Spinal cord mitochondria were able to retain considerably less calcium when administered as continuous infusion, which was not related to a general increased sensitivity of the mPT to calcium, its desensitization to calcium by the cyclophilin D inhibitor cyclosporin-A, or to differences in respiratory parameters. Spinal cord mitochondria maintained a higher concentration of extramitochondrial calcium during infusion than brain mitochondria possibly related to an increased set-point concentration for calcium uptake. A hampered transport and retention capacity of calcium may translate into an increased susceptibility of the spinal cord to neurodegenerative processes involving calcium-mediated damage.
线粒体通透性转换（mPT）是神经退行性变中的一种潜在致病机制。中枢神经系统（CNS）内不同区域对钙诱导的mPT表现出不同的敏感性，这可能与损伤后的易损性相关。例如，在肌萎缩侧索硬化症中脊髓具有选择性易损性，先前已证明源自脊髓的线粒体对mPT的敏感性增加。在本研究中，我们在取出CNS组织之前引入全身低温，以尽量减少在分离脊髓和脑皮质线粒体之前差异组织提取的影响。当连续输注时，脊髓线粒体保留钙的能力明显较低，这与mPT对钙的总体敏感性增加、亲环素D抑制剂环孢素A对钙的脱敏作用或呼吸参数的差异无关。在输注过程中，脊髓线粒体比脑线粒体维持更高浓度的线粒体外钙，这可能与钙摄取的设定点浓度增加有关。钙的转运和保留能力受阻可能转化为脊髓对涉及钙介导损伤的神经退行性过程的易感性增加。
