Aging of the liver: Age-associated mitochondrial damage in intact hepatocytes
Aging of the liver: Age-associated mitochondrial damage in intact hepatocytes
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DOI：
10.1002/hep.510240536
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发表时间：
1996-11-01
期刊：
影响因子：
13.5
通讯作者：
Vina, J
中科院分区：
文献类型：
--
作者：
Sastre, J;Pallardo, FV;Vina, J
线粒体损伤可能是细胞衰老的主要原因。到目前为止，这一假设仅用分离的线粒体进行了测试。本研究的目的是研究线粒体参与衰老使用整个肝细胞，而不是孤立的线粒体。使用现在的细胞仪，我们发现年龄与线粒体膜电位降低（30%），线粒体大小增加和线粒体过氧化物生成增加（23%）相关。细胞内过氧化物水平也增加。每个细胞的线粒体数量和线粒体内膜质量没有变化。从甘油或果糖（葡萄糖不依赖）的葡萄糖异生不随年龄变化，而从乳酸（葡萄糖依赖）。异生率的变化不伴随以下任何参数的变化：磷酸烯醇式丙酮酸羧激酶或丙酮酸羧化酶活性或线粒体ATP/ADP或细胞溶质NADH/NAD（+）比率。这是由于线粒体的苹果酸输出率降低（至对照组的20%）所致。线粒体苹果酸转运蛋白的损伤是转录后的，因为它在爪蟾卵母细胞中的表达使用多聚腺苷酸化的RNA从年轻或年老的动物的肝脏没有改变。油酸的生酮作用在老年大鼠的肝细胞中也有所下降。我们的研究结果表明，在完整的细胞中，年龄相关的细胞代谢障碍和线粒体功能和形态的特定变化之间的相关性，支持线粒体损伤在衰老中起关键作用的假设。
Mitochondrial damage may be a major cause of cellular aging. So far, this hypothesis had only been tested using isolated mitochondria. The aim of this study was to investigate the involvement of mitochondria in aging using whole liver cells and not isolated mitochondria only. Using now cytometry, we found that age is associated with a decrease in mitochondrial membrane potential (30%), an increase in mitochondrial size, and an increase in mitochondrial peroxide generation (23%). Intracellular peroxide levels were also increased. The number of mitochondria per cell and inner mitochondrial membrane mass did not change. Gluconeogenesis from glycerol or fructose (mitochondrial-independent) did not change with age, whereas it did from lactate (mitochondrial-dependent). The change in the rate of gluconeogenesis was not accompanied by changes in any of the following parameters: phosphoenolpyruvate carboxykinase or pyruvate carboxylase activities or mitochondrial ATP/ADP or cytosolic NADH/NAD(+) ratios. This was caused by a decreased rate of malate export (to 20% of the controls) from mitochondria. The impairment of the mitochondrial malate transporter is posttranscriptional because its expression in Xenopus oocytes using polyadenylated RNA from livers of young or old animals did not change. Ketogenesis from oleate also fell in hepatocytes from old rats. Our results show, for the first time in intact cells, a correlation between age-associated impairment of cell metabolism and specific changes in mitochondrial function and morphology, supporting the hypothesis that mitochondrial damage plays a key role in aging.