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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    • "SOD1 and SOD3 are Cu-Zn-SOD types, whereas SOD2 is Mn-SOD. Sirtuin, which was originally identified as a protein deacetylase[59], is also a regulator of the expression of cytoprotective enzymes such as SOD[60,61]and CAT (Fig. 4)[62]. Mammalian sirtuins consist of seven members (SIRT1–7), and have been implicated in various cellular responses including aging, transcription , apoptosis, and stress resistance[63]. "
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    ABSTRACT: It has been reported that reactive oxygen species (ROS), such as hydrogen peroxide and superoxide, take part in osteoclast differentiation as intra-cellular signaling molecules. The current assumed signaling cascade from RANK to ROS production is RANK, TRAF6, Rac1, and then Nox. The target molecules of ROS in RANKL signaling remain unclear; however, several reports support the theory that NF-κB signaling could be the crucial downstream signaling molecule of RANKL-mediated ROS signaling. Furthermore, ROS exert cytotoxic effects such as peroxidation of lipids and phospholipids and oxidative damage to proteins and DNA. Therefore, cells have several protective mechanisms against oxidative stressors that mainly induce cytoprotective enzymes and ROS scavenging. Three well-known mechanisms regulate cytoprotective enzymes including Nrf2-, FOXO-, and sirtuin-dependent mechanisms. Several reports have indicated a crosslink between FOXO- and sirtuin-dependent regulatory mechanisms. The agonists against the regulatory mechanisms are reported to induce these cytoprotective enzymes successfully. Some of them inhibit osteoclast differentiation and bone destruction via attenuation of intracellular ROS signaling. In this review article, we discuss the above topics and summarize the current information available on the relationship between cytoprotective enzymes and osteoclastogenesis.
    Full-text · Article · Jan 2016
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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.
    Full-text · Article · Apr 2015 · Free Radical Biology and Medicine
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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.
    Full-text · Article · Nov 2014 · Drug Discovery Today
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