Sirt3-Mediated Deacetylation of Evolutionarily Conserved Lysine 122 Regulates MnSOD Activity in Response to Stress

By Randa Tao, Mitchell C. Coleman, D. Pennington, Ozkan Ozden, S. Park, Haiyan Jiang, Hyunseok Kim, C. Flynn, S. Hill, W. H. McDonald and 3 more. Molecules and Cells, 2010

904 citations recorded by the source corpus.

Genetic deletion of the mitochondrial deacetylase sirtuin-3 (Sirt3) results in increased mitochondrial superoxide, a tumor permissive environment, and mammary tumor development. MnSOD contains a nutrient- and ionizing radiation (IR)-dependent reversible acetyl-lysine that is hyperacetylated in Sirt3−/− livers at 3 months of age. Livers of Sirt3−/− mice exhibit decreased MnSOD activity, but not immunoreactive protein, relative to wild-type livers. Re-introduction of wild-type, but not deacetylation null Sirt3, into Sirt3−/− MEFs deacetylated lysine and restored MnSOD activity. Site-directed mutagenesis of MnSOD lysine 122 to an arginine, mimicking deacetylation (lenti-MnSODK122-R), increased MnSOD activity when expressed in MnSOD−/− MEFs, suggesting acetylation directly regulates function. Furthermore, infection of Sirt3−/− MEFs with lenti-MnSODK122-R inhibited in vitro immortalization by an oncogene (Ras), inhibited IR-induced genomic instability, and decreased mitochondrial superoxide. Finally, IR was unable to induce MnSOD deacetylation or activity in Sirt3−/− livers and these irradiated livers displayed significant IR-induced cell damage and micro-vacuolization in their hepatocytes.

Subfields: Epidemiology, Geriatrics and Gerontology, Physiology

View Paper: https://www.semanticscholar.org/paper/169f708d4ef90894450d12216d018960419f7ee5

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Citations in the corpus

Circadian Clock NAD+ Cycle Drives Mitochondrial Oxidative Metabolism in Mice (2013, methodology): “mutant liver, we also observed increased acetylation at specific lysine residues within MnSOD (Lys(122)) (30) and IDH2 (Lys(413)) (31) that are”
CD38 dictates age-related NAD decline and mitochondrial dysfunction through a SIRT3-dependent mechanism (2016, neutral): “SIRT3 is one of the sirtuins localized in mitochondria that regulate key mitochondrial proteins important for metabolism and oxidative homeostasis such as LCAD, IDH2, SDH, and MnSOD (Finley et al., 2011; Hirschey et al., 2010; Shimazu et al., 2010; Tao et al., 2010; Yu et al., 2012).”
SIRT3 opposes reprogramming of cancer cell metabolism through HIF1α destabilization (2011, background): “Additionally, SIRT3 can directly target IDH2, influencing cellular redox status, and SOD2, activating mitochondrial ROS scavenging (Qiu et al., 2010; Someya et al., 2010; Tao et al., 2010).”
SIRT3 Deficiency and Mitochondrial Protein Hyperacetylation Accelerate the Development of the Metabolic Syndrome (2011, neutral): “, 2008), and increased reactive oxygen species (Kim et al., 2010; Qiu et al., 2010; Someya et al., 2010; Tao et al., 2010).”
Lysine succinylation is a frequently occurring modification in prokaryotes and eukaryotes and extensively overlaps with acetylation. (2013, background): “, 2010); and super oxide dismutase (SOD2) lysines 68, 122, and 130 (Chen et al., 2011; Tao et al., 2010).”
The hallmarks of aging. (2013, background): “SIRT3 may also directly control the rate of ROS production by deacetylating manganese superoxide dismutase, a major mitochondrial antioxidant enzyme (Qiu et al., 2010; Tao et al., 2010).”