Arai M, Leo M A, Nakano M, Gordon E R, Lieber C S
Hepatology. 1984 Mar-Apr;4(2):165-74. doi: 10.1002/hep.1840040201.
Baboons fed ethanol (50% of total calories) chronically develop ultrastructural alterations of hepatic mitochondria. To determine whether mitochondrial functions are also altered, mitochondria were isolated from nine baboons fed ethanol chronically and their pair-fed controls. At the fatty liver stage, ADP-stimulated respiration was depressed in ethanol-fed baboons by 59.4% with glutamate, 43.2% with acetaldehyde, 45.1% with succinate and 51.1% with ascorbate as substrates. A similar decrease was noted in the ADP/O ratio (14 to 28%) and respiratory control ratio (20 to 44%) with all substrates. Similar alterations of mitochondrial functions were observed in baboons with more advanced stages of liver disease, namely fibrosis. These changes after ethanol treatment were associated with decreases in the enzyme activities of mitochondrial respiratory chain: glutamate, NADH and succinate dehydrogenase (42, 24 and 28%, respectively), glutamate-, NADH- or succinate-cytochrome c reductase (42, 27 and 32%, respectively) and cytochrome oxidase (59.6%). The content of all cytochromes was also decreased in ethanol-fed baboons, especially aa3 (57%). Moreover, [14C]leucine incorporation into mitochondrial membranes was depressed by 21% after ethanol treatment. On the other hand, glutamate dehydrogenase activities of serum and cytosol in ethanol-fed baboons were significantly higher than those in pair-fed controls. Morphologically, mitochondria of ethanol-fed baboons were larger than those of pair-fed controls. However, the mitochondrial protein content per mitochondrial DNA was unchanged. From these results, we conclude that, morphologically and functionally, hepatic mitochondria in baboons are altered by chronic ethanol consumption; it is noteworthy that these changes are fully developed already at the fatty liver stage, and that morphological alteration appears to reflect the damage of mitochondrial membranes rather than an adaptive hypertrophy.
长期喂食乙醇（占总热量的50%）的狒狒会出现肝线粒体的超微结构改变。为了确定线粒体功能是否也发生改变，从9只长期喂食乙醇的狒狒及其配对喂食的对照动物中分离出线粒体。在脂肪肝阶段，以谷氨酸、乙醛、琥珀酸和抗坏血酸为底物时，喂食乙醇的狒狒中ADP刺激的呼吸作用分别降低了59.4%、43.2%、45.1%和51.1%。所有底物的ADP/O比值（降低14%至28%）和呼吸控制率（降低20%至44%）也出现了类似程度的下降。在患有更晚期肝病（即肝纤维化）的狒狒中也观察到了类似的线粒体功能改变。乙醇处理后的这些变化与线粒体呼吸链酶活性的降低有关：谷氨酸、NADH和琥珀酸脱氢酶（分别降低42%、24%和28%），谷氨酸 - 、NADH - 或琥珀酸 - 细胞色素c还原酶（分别降低42%、27%和32%）以及细胞色素氧化酶（降低59.6%）。喂食乙醇的狒狒中所有细胞色素的含量也降低了，尤其是aa3（降低57%）。此外，乙醇处理后线粒体膜中[14C]亮氨酸的掺入量降低了21%。另一方面，喂食乙醇的狒狒血清和细胞溶质中的谷氨酸脱氢酶活性显著高于配对喂食的对照动物。从形态学上看，喂食乙醇的狒狒的线粒体比配对喂食的对照动物的线粒体更大。然而，每个线粒体DNA的线粒体蛋白含量没有变化。从这些结果中，我们得出结论，长期摄入乙醇会在形态和功能上改变狒狒的肝线粒体；值得注意的是，这些变化在脂肪肝阶段就已充分显现，而且形态学改变似乎反映的是线粒体膜的损伤而非适应性肥大。
