Age-associated increases in oxidative stress and antioxidant enzyme activities in cardiac interfibrillar mitochondria: implications for the mitochondrial theory of aging
Age-associated increases in oxidative stress and antioxidant enzyme activities in cardiac interfibrillar mitochondria: implications for the mitochondrial theory of aging
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DOI：
10.1096/fj.04-2622fje
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发表时间：
2005-01-01
期刊：
影响因子：
4.8
通讯作者：
Leeuwenburgh, C
中科院分区：
文献类型：
--
作者：
Judge, S;Jang, YM;Leeuwenburgh, C
线粒体功能障碍和大分子氧化损伤的积累被认为在衰老过程中起关键作用。心肌中存在两种不同的线粒体：肌层下线粒体（SSM）和纤维间线粒体（IFM），这一事实使心肌线粒体年龄相关变化的表征变得复杂。我们研究了从幼年（6月龄）和老年（24月龄）雄性fisher -344大鼠分离的SSM和IFM在过氧化氢生成（H2O2）和氧化应激方面是否存在差异。随着年龄的增长，IFM的氧化应激水平（4-羟基-2-壬烯醛修饰蛋白、蛋白羰基和丙二醛）显著增加。相反，随着年龄的增长，SSM中只有蛋白质羰基升高。IFM中MnSOD、GPX和CAT活性随年龄显著升高，而SSM中MnSOD和GPX活性随年龄升高而下降。这些抗氧化酶活性的增加可能是对线粒体产生超氧化物和过氧化氢增加的反应。事实上，随着年龄的增长，SSM产生更多的H2O2，而IFM的增加并不显著，但这可能是由于IFM比SSM观察到更高的抗氧化酶活性。最后，在年轻和年老的大鼠中，与SSM相比，IFM中还原谷胱甘肽水平显著降低，而谷胱甘肽还原酶活性与年龄或线粒体亚群没有差异，表明谷胱甘肽的消耗增加。IFM中氧化损伤的积累可能是心肌功能年龄相关改变的一个主要因素。我们的结果强调了在试图阐明线粒体功能障碍对心肌衰老的贡献时，研究两种线粒体种群的重要性。
Mitochondrial dysfunction and the accumulation of oxidative damage to macromolecules are believed to play key roles in the aging process. Characterization of age-related changes to cardiac mitochondria has been complicated by the fact that two distinct populations of mitochondria exist in the myocardium: subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM). We investigated whether differences in hydrogen peroxide production (H2O2) and oxidative stress existed between cardiac SSM and IFM isolated from young ( 6 mo) and old ( 24 mo) male Fischer-344 rats. There was a significant increase in oxidative stress levels (4-hydroxy-2-nonenal-modified proteins, protein carbonyls, and malondialdehyde) in IFM with age. In contrast, only protein carbonyls were elevated in SSM with age. Significant age-related increases in MnSOD, GPX, and CAT activities were detected in IFM, while in SSM, MnSOD, and GPX activities increased with age and CAT activity declined. These increases in antioxidant enzyme activity likely occurred in response to increased mitochondrial production of superoxide and hydrogen peroxide. Indeed, SSM produced more H2O2 with age, while the increase in IFM was not significant, but this may be due to the higher antioxidant enzyme activity observed in IFM compared with SSM. Finally, reduced glutathione levels were significantly lower in IFM compared with SSM in both young and old rats, while glutathione reductase activity was not different with age or mitochondrial subpopulations, indicating increased consumption of glutathione. The accumulation of oxidant-induced damage in IFM may be a major contributing factor to the age-related alterations in myocardial function. Our results emphasize the importance of studying both mitochondrial populations when attempting to elucidate the contribution of mitochondrial dysfunction to myocardial aging.