Siakotos A N, Blair P S, Savill J D, Katz M L
Department of Pathology-Laboratory Medicine, Indiana University School of Medicine, Indianapolis 46202-5122, USA.
Neurochem Res. 1998 Jul;23(7):983-9. doi: 10.1023/a:1021036506299.
The neuronal ceroid-lipofuscinoses (NCL) are a group of autosomal recessively inherited neurodegenerative disorders characterized by progressive dementia, neuronal atrophy, and premature death. The late infantile and juvenile types of NCL show massive accumulation of mitochondrial ATP synthase subunit c protein in both mitochondria and lysosomes. The specific accumulation of this mitochondrial protein suggests that mitochondrial function may be impaired in the NCL diseases. Therefore, a study was conducted to determine whether oxidative phosphorylation is altered in liver mitochondria from English setters with NCL, an animal model in which there is also massive accumulation of the subunit c protein. The ADP/O ratios were significantly depressed in affected and carrier dogs, suggesting that the disease mutation led to a partial uncoupling of oxidative phosphorylation. On the other hand, ADP-stimulated respiration rates were higher than normal in both carriers and affected dogs. The increased respiration rates were highest in the carriers, and may reflect a compensatory response to the reduced efficiency of oxidative phosphorylation. Accompanying the increased respiration rates were elevations in mitochondrial ADP content with the elevation being greater in the carriers than in the affected dogs. This suggests that the increased respiration rates may be due, at least in part, to enhanced ADP uptake by the mitochondria. In the carriers, the enhanced respiration rate may be sufficient to offset the reduced efficiency of oxidative phosphorylation. In the affected animals, which had lower respiration rates than the carriers, the enhanced respiration rates may not be sufficient to offset the reduced efficiency of oxidative phosphorylation. Impaired mitochondrial function may therefore contribute to the disease pathology.
神经元蜡样脂褐质沉积症（NCL）是一组常染色体隐性遗传的神经退行性疾病，其特征为进行性痴呆、神经元萎缩和过早死亡。NCL的晚婴儿型和青少年型在线粒体和溶酶体中均显示出线粒体ATP合酶c亚基蛋白的大量积累。这种线粒体蛋白的特异性积累表明线粒体功能可能在NCL疾病中受损。因此，开展了一项研究，以确定患有NCL的英国塞特犬肝脏线粒体中的氧化磷酸化是否发生改变，该动物模型中也存在亚基c蛋白的大量积累。在患病犬和携带犬中，ADP/O比率显著降低，表明疾病突变导致氧化磷酸化部分解偶联。另一方面，在携带犬和患病犬中，ADP刺激的呼吸速率均高于正常水平。携带犬的呼吸速率增加最高，可能反映了对氧化磷酸化效率降低的一种代偿反应。伴随呼吸速率增加的是线粒体ADP含量的升高，携带犬中的升高幅度大于患病犬。这表明呼吸速率增加可能至少部分是由于线粒体对ADP摄取增强所致。在携带犬中，增强的呼吸速率可能足以抵消氧化磷酸化效率的降低。在呼吸速率低于携带犬的患病动物中，增强的呼吸速率可能不足以抵消氧化磷酸化效率的降低。因此，线粒体功能受损可能导致疾病病理变化。
