Liu Jiankang, Atamna Hani, Kuratsune Hirohiko, Ames Bruce N
Division of Biochemistry and Molecular Biology, University of California, Berkeley, California 94720, USA.
Ann N Y Acad Sci. 2002 Apr;959:133-66. doi: 10.1111/j.1749-6632.2002.tb02090.x.
Mitochondria decay with age due to the oxidation of lipids, proteins, RNA, and DNA. Some of this decay can be reversed in aged animals by feeding them the mitochondrial metabolites acetylcarnitine and lipoic acid. In this review, we summarize our recent studies on the effects of these mitochondrial metabolites and mitochondrial antioxidants (alpha-phenyl-N-t-butyl nitrone and N-t-butyl hydroxylamine) on the age-associated mitochondrial decay of the brain of old rats, neuronal cells, and human diploid fibroblast cells. In feeding studies in old rats, these mitochondrial metabolites and antioxidants improve the age-associated decline of ambulatory activity and memory, partially restore mitochondrial structure and function, inhibit the age-associated increase of oxidative damage to lipids, proteins, and nucleic acids, elevate the levels of antioxidants, and restore the activity and substrate binding affinity of a key mitochondrial enzyme, carnitine acetyltransferase. These mitochondrial metabolites and antioxidants protect neuronal cells from neurotoxin- and oxidant-induced toxicity and oxidative damage; delay the normal senescence of human diploid fibroblast cells, and inhibit oxidant-induced acceleration of senescence. These results suggest a plausible mechanism: with age, increased oxidative damage to proteins and lipid membranes, particularly in mitochondria, causes a deformation of structure of enzymes, with a consequent decrease of enzyme activity as well as substrate binding affinity for their substrates; an increased level of substrate restores the velocity of the reaction and restores mitochondrial function, thus delaying mitochondrial decay and aging. This loss of activity due to coenzyme or substrate binding appears to be true for a number of other enzymes as well, including mitochondrial complex III and IV.
随着年龄增长，线粒体因脂质、蛋白质、RNA和DNA的氧化而衰退。通过给老年动物喂食线粒体代谢物乙酰肉碱和硫辛酸，这种衰退的一部分可以得到逆转。在这篇综述中，我们总结了我们最近关于这些线粒体代谢物和线粒体抗氧化剂（α-苯基-N-叔丁基硝酮和N-叔丁基羟胺）对老年大鼠大脑、神经元细胞和人二倍体成纤维细胞与年龄相关的线粒体衰退影响的研究。在对老年大鼠的喂养研究中，这些线粒体代谢物和抗氧化剂改善了与年龄相关的自主活动和记忆力下降，部分恢复了线粒体结构和功能，抑制了与年龄相关的脂质、蛋白质和核酸氧化损伤的增加，提高了抗氧化剂水平，并恢复了关键线粒体酶肉碱乙酰转移酶的活性和底物结合亲和力。这些线粒体代谢物和抗氧化剂保护神经元细胞免受神经毒素和氧化剂诱导的毒性和氧化损伤；延缓人二倍体成纤维细胞的正常衰老，并抑制氧化剂诱导的衰老加速。这些结果提示了一种合理的机制：随着年龄增长，蛋白质和脂质膜尤其是线粒体中的氧化损伤增加，导致酶结构变形，从而导致酶活性以及底物对其底物的结合亲和力降低；底物水平的增加恢复了反应速度并恢复了线粒体功能，从而延缓了线粒体衰退和衰老。由于辅酶或底物结合导致的这种活性丧失似乎对许多其他酶也是如此，包括线粒体复合物III和IV。
