Molecular analysis of the role of mitochondria in aging and lengevity
Kashyap B Choksi
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The Free Radical Theory of Aging states that there is an increase in reactive oxygen species (ROS) production with aging leading to increase in tissue dysfunction. Mitochondria are the major source of ROS, which damages essential macromolecules by oxidative modification and may lead to mitochondrial dysfunction. Accumulation of oxidative damage caused by ROS has been implicated as a major causal factor in the age-associated decline in tissue function and implicated in many age-associated diseases and sarcopenia. Mitochondrial electron transport chain (ETC) complexes I and III are the principle sites of ROS production, and oxidative modifications to their complex subunits inhibit their in vitro activity. Therefore, we hypothesize that mitochondrial complex subunits are primary targets for oxidative damage which may impair their structure/function leading to mitochondrial dysfunction associated with aging.\r\n In addition, numerous studies have identified long-lived mutant mice (i.e., Ames dwarf mice) that suggest that their longevity correlates with oxidative stress resistance. It has not yet been determined whether the mutant mice have inherently lower levels of ROS and whether there are changes in the electron transport chain function compared to wild-type. Therefore, we hypothesize that the dwarf mice have lower levels of ROS-generated lipid peroxidation markers and there are age-related changes in ETC function from tissues of dwarf and wild-type that may play a role in longevity.\r\n In our studies, we have developed a novel methodology for detecting oxidative modification markers using bovine heart mitochondria. In addition, we found that in various mouse tissues ETC proteins are specifically targeted for oxidation and in most cases increased oxidative modifications with aging correlate with decreased enzymatic activities. Thus, we propose that the specificity of the oxidative modification may play a key role in predicting the consequences of ROS-mediate damage. The results from long-lived Ames dwarf mice show that they have lower levels of ROS markers suggesting delayed aging characteristics and except for kidney very little changes in ETC function are noted. Therefore, our studies provide important insight into physiological effects of oxidative modifications on mitochondrial function as well as role of oxidative stress markers in aging and longevity.