Acetylation of MnSOD directs enzymatic activity responding to cellular nutrient status or oxidative stress

Departments of Cancer Biology, Pediatrics, and Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Aging (Impact Factor: 6.43). 02/2011; 3(2):102-7.
Source: PubMed


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.

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Available from: Ozkan Ozden, Dec 19, 2014
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    • "In various studies, many investigators have characterized different SOD2 mutants to illustrate the biological function and structure–activity relationship of SOD2; however, nobody has acquired a mutant with activity higher than that of wild-type SOD2 [11] [12] [13] [14] [15]. In recent years, several studies have reported that the antioxidative activity of the SOD2 is regulated by many posttranslational modifications (PTMs), including acetylation [16] [17], methylation [18], phosphorylation [19], nitration [14] [20], and glutathionylation [20]. These explorations have provided new methods to possibly obtain a higher-activity mutant form of SOD2 by changing the PTMs in SOD2. "
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    ABSTRACT: Superoxide is the primary reactive oxygen species generated in the mitochondria. Manganese superoxide dismutase (SOD2) is the major enzymatic superoxide- scavenger present in the mitochondrial matrix and one of the most crucial reactive oxygen species (ROS)-scavenging enzymes in the cell. SOD2 is activated by Sirtuin 3 (SIRT3) through NAD(+)-dependent deacetylation. However, the exact acetylation sites of SOD2 are ambiguous and the mechanisms underlying the deacetylation-mediated SOD2 activation largely remain unknown. We are the first to characterize the SOD2 mutants of the acetylation sites by investigating the relative enzymatic activity, structures, and electrostatic potential of the SOD2 in this study. These SOD2 mutations affected the superoxide-scavenging activity in vitro and in HEK293T cells. The lysine 68 (K68) site is the most important acetylation site contributing to SOD2 activation and plays a role on cell survival after paraquat treatment. The molecular basis underlying the regulation of SOD2 activity by K68 was investigated in detail. Molecular dynamics simulations revealed that K68 mutations induced a conformational shift of residues located in the active center of SOD2 and altered the charge distribution on the SOD2 surface. Thus, the entry of the superoxide anion into the coordinated core of SOD2 was inhibited. Our results provided a novel mechanistic insight, where SOD2 acetylation affected the structure and charge distribution of the SOD2, the tetramerization and p53-SOD2 interactions of the SOD2 in the mitochondria, which may play a role in nuclear-mitochondria communication during aging. Copyright © 2015. Published by Elsevier Inc.
    Free Radical Biology and Medicine 04/2015; 85. DOI:10.1016/j.freeradbiomed.2015.04.011 · 5.74 Impact Factor
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    • "Mutations within the MnSOD gene and its regulatory sequence have been observed in several types of human cancers [5,38–40]. In addition to cancer, mutations in MnSOD are associated with cardiomyopathy and neuronal diseases, demonstrating the significant role of MnSOD activity in agerelated illnesses [6]. "
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    ABSTRACT: Reactive oxygen species (ROS) and reactive nitrogen species (RNS) participate in pathological tissue damage. Mitochondrial manganese superoxide dismutase (MnSOD) normally keeps ROS and RNS in check. During development of mangafodipir (MnDPDP) as a magnetic resonance imaging (MRI) contrast agent, it was discovered that MnDPDP and its metabolite manganese pyridoxyl ethyldiamine (MnPLED) possessed SOD mimetic activity. MnDPDP has been tested as a chemotherapy adjunct in cancer patients and as an adjunct to percutaneous coronary intervention in patients with myocardial infarctions, with promising results. Whereas MRI contrast depends on release of Mn2+, the SOD mimetic activity depends on Mn2+ that remains bound to DPDP or PLED. Calmangafodipir [Ca4Mn(DPDP)5] is stabilized with respect to Mn2+ and has superior therapeutic activity. Ca4Mn(DPDP)5 is presently being explored as a chemotherapy adjunct in a clinical multicenter Phase II study in patients with metastatic colorectal cancer.
    Drug Discovery Today 11/2014; 20(4). DOI:10.1016/j.drudis.2014.11.008 · 6.69 Impact Factor
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    • "Although the mechanism(s) by which loss of Sirt3 results in a tumor-permissive phenotype is complex, one interesting, and perhaps informative, observation is that mice lacking Sirt3 have biochemical features similar to the Warburg effect [21]. For example, Sirt3 À /À mouse embryonic fibroblasts (MEFs) consumed more glucose and produced more lactate than wild-type cells [15] [17] [18] [21] [23]. In addition, overexpression of SIRT3 in vitro was sufficient to reverse this metabolic shift [24]. "
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    ABSTRACT: Pyruvate dehydrogenase E1 alpha (PDHE1α or PDHA1) is the first component enzyme of the pyruvate dehydrogenase (PDH) complex (PDC) that transforms pyruvate, via pyruvate decarboxylation, into acetyl-CoA that is subsequently used by both the citric acid cycle and oxidative phosphorylation to generate ATP. As such, PDH links glycolysis and oxidative phosphorylation in normal as well as cancer cells. Herein we report that SIRT3 interacts with PDHA1 and directs its enzymatic activity via changes in protein acetylation. SIRT3 deacetylates PDHA1 lysine 321 (K321) and a PDHA1 mutant, mimicking a deacetylated lysine (PDHA1(K321R)) increases in PDH activity, as compared to the K321 acetylation mimic (PDHA1(K321Q)) or wild-type PDHA1. Finally, PDHA1(K321Q) exhibited a more transformed in vitro cellular phenotype as compared to PDHA1(K321R). These results suggest that the acetylation of PDHA1 provides another layer of enzymatic regulation, in addition to phosphorylation, involving a reversible acetyl-lysine suggesting that the acetylome, as well as the kinome, links glycolysis to respiration.
    Free Radical Biology and Medicine 08/2014; 76. DOI:10.1016/j.freeradbiomed.2014.08.001 · 5.74 Impact Factor
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