Manganese superoxide dismutase is a mitochondrial fidelity protein that protects Polγ against UV-induced inactivation.

Published

Journal Article

Manganese superoxide dismutase is a nuclear encoded primary antioxidant enzyme localized exclusively in the mitochondrial matrix. Genotoxic agents, such as ultraviolet (UV) radiation, generates oxidative stress and cause mitochondrial DNA (mtDNA) damage. The mtDNA polymerase (Polγ), a major constituent of nucleoids, is responsible for the replication and repair of the mitochondrial genome. Recent studies suggest that the mitochondria contain fidelity proteins and MnSOD constitutes an integral part of the nucleoid complex. However, it is not known whether or how MnSOD participates in the mitochondrial repair processes. Using skin tissue from C57BL/6 mice exposed to UVB radiation, we demonstrate that MnSOD has a critical role in preventing mtDNA damage by protecting the function of Polγ. Quantitative-PCR analysis shows an increase in mtDNA damage after UVB exposure. Immunofluorescence and immunoblotting studies demonstrate p53 translocation to the mitochondria and interaction with Polγ after UVB exposure. The mtDNA immunoprecipitation assay with Polγ and p53 antibodies in p53(+/+) and p53(-/-) mice demonstrates an interaction between MnSOD, p53 and Polγ. The results suggest that these proteins form a complex for the repair of UVB-associated mtDNA damage. The data also demonstrate that UVB exposure injures the mtDNA D-loop in a p53-dependent manner. Using MnSOD-deficient mice we demonstrate that UVB-induced mtDNA damage is MnSOD dependent. Exposure to UVB results in nitration and inactivation of Polγ, which is prevented by addition of the MnSOD mimetic Mn(III)TE-2-PyP(5+). These results demonstrate for the first time that MnSOD is a fidelity protein that maintains the activity of Polγ by preventing UVB-induced nitration and inactivation of Polγ. The data also demonstrate that MnSOD has a role along with p53 to prevent mtDNA damage.

Full Text

Duke Authors

Cited Authors

  • Bakthavatchalu, V; Dey, S; Xu, Y; Noel, T; Jungsuwadee, P; Holley, AK; Dhar, SK; Batinic-Haberle, I; St Clair, DK

Published Date

  • April 26, 2012

Published In

Volume / Issue

  • 31 / 17

Start / End Page

  • 2129 - 2139

PubMed ID

  • 21909133

Pubmed Central ID

  • 21909133

Electronic International Standard Serial Number (EISSN)

  • 1476-5594

Digital Object Identifier (DOI)

  • 10.1038/onc.2011.407

Language

  • eng

Conference Location

  • England