Mnsod lysine 68 acetylation leads to cisplatin and doxorubicin resistance due to aberrant mitochondrial metabolism

Yucheng Gao, Yueming Zhu, Elizabeth L. Tran, Valerie Tokars, Angela E. Dean, Songhua Quan, David R Gius*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Manganese superoxide dismutase (MnSOD) acetylation (Ac) has been shown to be a key posttranslational modification important in the regulation of detoxification activity in various disease models. We have previously demonstrated that MnSOD lysine-68 (K68) acetylation (K68-Ac) leads to a change in function from a superoxide-scavenging homotetramer to a peroxidase-directed monomer. Here, we found that estrogen receptor positive (ER+) breast cancer cell lines (MCF7 and T47D), selected for continuous growth in cisplatin (CDDP) and doxorubicin (DXR), exhibited an increase in MnSODK68-Ac. In addition, MnSOD-K68-Ac, as modeled by the expression of a validated acetylation mimic mutant gene (MnSODK68Q), also led to therapy resistance to CDDP and DXR, altered mitochondrial structure and morphology, and aberrant cellular metabolism. MnSODK68Q expression in mouse embryo fibroblasts (MEFs) induced an in vitro transformation permissive phenotype. Computerized molecular protein dynamics analysis of both MnSOD-K68-Ac and MnSOD-K68Q exhibited a significant change in charge distribution along the α1 and α2 helices, directly adjacent to the Mn2+ binding site, implying that this decrease in surface charge destabilizes tetrameric MnSOD, leading to an enrichment of the monomer. Finally, monomeric MnSOD, as modeled by amber codon substitution to generate MnSODK68-Ac or MnSOD-K68Q expression in mammalian cells, appeared to incorporate Fe to maximally induce its peroxidase activity. In summary, these findings may explain the mechanism behind the observed structural and functional change of MnSOD-K68-Ac.

Original languageEnglish (US)
Pages (from-to)1203-1216
Number of pages14
JournalInternational Journal of Biological Sciences
Volume17
Issue number5
DOIs
StatePublished - 2021

Keywords

  • Acetylation
  • Acetylome
  • Aging
  • Carcinogenesis
  • Lysine 68
  • Metabolism
  • Mitochondria
  • MnSOD
  • Signaling
  • SIRT3
  • Sirtuins
  • SOD2

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Applied Microbiology and Biotechnology
  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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