Manganese superoxide dismutase is a mitochondrial fidelity protein that protects Polγ against UV-induced inactivation.
Manganese superoxide dismutase is a mitochondrial fidelity protein that protects Polγ against UV-induced inactivation.
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DOI：
10.1038/onc.2011.407
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发表时间：
2012-04-26
期刊：
影响因子：
8
通讯作者：
St Clair, D. K.
中科院分区：
文献类型：
--
作者：
Bakthavatchalu, V.;Dey, S.;Xu, Y.;Noel, T.;Jungsuwadee, P.;Holley, A. K.;Dhar, S. K.;Batinic-Haberle, I.;St Clair, D. K.
锰超氧化物歧化酶是一种核编码的初级抗氧化酶，只定位于线粒体基质中。基因毒性物质，如紫外线辐射，会产生氧化应激并导致线粒体DNA （mtDNA）损伤。线粒体DNA聚合酶（Polγ）是类核的主要组成部分，负责线粒体基因组的复制和修复。最近的研究表明，线粒体含有保真蛋白，而MnSOD是类核复合体的组成部分。然而，目前尚不清楚MnSOD是否或如何参与线粒体修复过程。使用暴露于UVB辐射的C57/BL6小鼠皮肤组织，我们证明MnSOD通过保护Polγ的功能在防止mtDNA损伤中起关键作用。Q-PCR分析显示，UVB暴露后mtDNA损伤增加。免疫荧光和免疫印迹研究表明，在UVB暴露后，p53易位至线粒体并与Polγ相互作用。在p53+/+和p53 - / -小鼠中，用Polγ和p53抗体的mtDNA免疫沉淀试验表明MnSOD、p53和Polγ之间存在相互作用。结果表明，这些蛋白质形成了一种复合物，用于修复uvb相关的mtDNA损伤。数据还表明，UVB暴露以p53依赖的方式损伤mtDNA d -环。使用mnsod缺失小鼠，我们证明了uvb诱导的mtDNA损伤是mnsod依赖的。暴露于UVB会导致Polγ的硝化和失活，这可以通过添加MnSOD模拟物mniite -2- pyp5 +来阻止。这些结果首次证明MnSOD是一种保真蛋白，通过阻止uvb诱导的Polγ硝化和失活来维持Polγ的活性。数据还表明，MnSOD与p53一起发挥作用，防止mtDNA损伤。
Manganese superoxide dismutase is a nuclear encoded primary antioxidant enzyme localized exclusively in the mitochondrial matrix. Genotoxic agents, such as UV radiation, generates oxidative stress and cause mitochondrial DNA (mtDNA) damage. The mitochondrial DNA polymerase (Polγ), a major constituent of nucleoids, is responsible for the replication and repair of the mitochondrial genome. Recent studies suggest that 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 C57/BL6 mice exposed to UVB radiation, we demonstrate that MnSOD plays a critical role in preventing mtDNA damage by protecting the function of Polγ. Q-PCR analysis shows an increase in mtDNA damage after UVB exposure. Immunofluorescence and immunoblotting studies demonstrate p53 translocation to 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 MnIIITE-2-PyP5+. 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 plays a role along with p53 to prevent mtDNA damage.
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