Lysine 68 Acetylation Regulates the Dichotomous Role of MnSOD: a Protective Tetrameric Detoxification Complex Versus a Monomeric Oncoprotein

Mammalian MnSOD is a mitochondrial matrix-localized, homotetrameric, antioxidant enzyme, and its primary function is to scavenge superoxide generated from different metabolic processes. Recent studies showed that MnSOD lysine 68 (K68) can be acetylated and may affect normal MnSOD function. However, the specific cell biological, biochemical, and/or physiological significance of K68, as well as the underlying molecular mechanism by which they regulate MnSOD detoxification activity and mitochondrial metabolism, remains to be fully determined. In this regard, we presented data showing that MnSOD-K68 acetylation (K68-Ac), directs ROS detoxification activity, as well as connects metabolic stress and mitochondrial reparative pathways that maintain metabolic balance. Our results show that K68-Ac leads to a monomer form of MnSOD that functions as a peroxidase, different from the well-established tetramer form, which acts as a superoxide dismutase. The peroxidase activity of monomeric MnSOD was determined using tissue culture IP experiments, as well as by amber-suppression technology for the site-specific incorporation of N-(ϵ)-acetyl-l-lysine using a bacterial system. We also show that enforced expression of MnSODK68Q (the acetylation mimic mutant gene) transforms wild-type primary mouse embryonic fibroblasts (pMEFs) when co-infected with either c-Myc or Ras, as measured by in vitro transformation assays and xenograft formation. In addition, MCF7 and T47D cells, as well as immortalized MnSOD-/- mouse embryonic fibroblasts (MEFs), expressing MnSODK68Q also exhibited a more aggressive in vitro transformation permissive phenotype. Finally, tamoxifen resistant MCF7 and T47D cells, selected by three months of growth in tamoxifen, displayed a MnSOD-K68-Ac tumor signature. In conclusion, our results suggest that acetylation status of MnSOD K68 functions as a molecular switch directing whether MnSOD is a protective tetrameric superoxide detoxification complex when deacetylated, and in contrast, when MnSOD is acetylated, it functions as a monomeric peroxidase enzyme that promoters an oncogenic permissive phenotype, as well as contributes to resistance to endocrine therapy.