Abstract
A fundamental observation in biology is that mitochondrial function, as measured by increased reactive oxygen species (ROS), changes significantly with age, suggesting a potential mechanistic link between the cellular processes governing longevity and mitochondrial metabolism homeostasis. In addition, it is well established that altered ROS levels are observed in multiple age-related illnesses including carcinogenesis, neurodegenerative, fatty liver, insulin resistance, and cardiac disease, to name just a few. Manganese superoxide dismutase (MnSOD) is the primary mitochondrial ROS scavenging enzyme that converts superoxide to hydrogen peroxide, which is subsequently converted to water by catalase and other peroxidases. It has recently been shown that MnSOD enzymatic activity is regulated by the reversible acetylation of specific, evolutionarily conserved lysine(s) in the protein. These results, suggest for the first time, that the mitochondria contain bidirectional post-translational signaling networks, similar to that observed in the cytoplasm and nucleus, and that changes in lysine acetylation alter MnSOD enzymatic activity. In addition, these new results demonstrate that the mitochondrial anti-aging or fidelity / sensing protein, SIRT3, responds to changes in mitochondrial nutrient and/or redox status to alter the enzymatic activity of specific downstream targets, including MnSOD that adjusts and/or maintains ROS levels as well as metabolic homeostatic poise.
Highlights
One theme that has emerged in the last several years is that aging, perhaps better defined as longevity, is a complex genetic and cellular process that appears to be regulated, at least in part, by a relatively new gene family referred to as sirtuins [1,2]
We have previously demonstrated that MEFs lacking Sirt3 exhibit an immortalization permissive phenotype and the knockout mice spontaneously form well differentiated, estrogen and progesterone (ER/PR)positive mammary tumors [18]
These results suggest that the aberrant regulation of the mitochondrial acetylome, which by definition occurs in murine cells lacking Sirt3, results in a phenotype permissive for mouse conditions that mimic human illness as well as suggest an underlying mechanism involving increased reactive oxygen species (ROS) and superoxide levels
Summary
One theme that has emerged in the last several years is that aging, perhaps better defined as longevity, is a complex genetic and cellular process that appears to be regulated, at least in part, by a relatively new gene family referred to as sirtuins [1,2]. Three of the seven mammalian sirtuins appear to be localized to the mitochondria [11], including SIRT3 that is the primary mitochondrial deacetylase [17], suggesting a significant role for these sirtuins in regulating mitochondrial metabolism [12,17].
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