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Start of funding 01.01.2009
The role of oxidative stress on the glycation of cytosolic proteins, mitochondrial DNA, and genomic DNA in vitro and in vivo
Prof. Dr. Monika Pischetsrieder
Friedrich-Alexander-University of Erlangen-Nuremberg
Lehrstuhl für Lebensmittelchemie
Dr. Ting-Ting Huang
Stanford University
Department of Neurology - Lucile Packer Children's Hospital
Advanced glycation end-products (AGEs) accumulate during aging as well as in different metabolic disorders such as diabetes and uremia and are associated with pathological complications. In order to find efficient means to inhibit AGE formation, the molecular mechanism of glycation must be elucidated. Our own work and work from others provide growing evidence that oxidative stress is a major parameter for AGE formation in vivo and in vitro. The aim of this project is therefore to investigate the role of reactive oxidative species in the cellular formation of AGEs. In order to study the role of oxidative stress in vivo, animal models with altered levels of antioxidant enzymes are often used. Experiments will be carried out at the Institute of Neurology and Neurological Sciences at Stanford University to analyze glycation of cellular proteins, mitochondrial DNA, and genomic DNA in transgenic mice with decreased levels of Cu,ZnSOD and MnSOD.
Final report:
The accumulation of somatic mutations in mitochondrial DNA induced by oxidative stress is regarded as a major contributor of aging and age-related diseases. The present project investigated mechanisms of oxidative damage to mitochondrial DNA. For this purpose, primary mouse cells were used, which express only very low levels of manganese superoxide dismutase. This antioxidative enzyme is specifically located in the mitochondria. Consequently, the cell model is ideal to study oxidative damage to mitochondrial DNA in the natural, cellular environment.
Thus, N2-carboxyethyl-2‘-deoxyguanosine (CEdG) was identified as a novel DNA-adduct, which is formed by oxidative damage of mitochondrial DNA. Since CEdG impairs DNA integrity and gene function, it may be an important contributor of the loss of mitochondrial function during ageing. Consequently, inhibitors of CEdG-formation could be interesting potential drugs against age-related degenerative diseases.
The results of the study were published: Breyer V, Huang, TT, Pischetsrieder M (2012) Endogenous mitochondrial oxidative stress in MnSOD deficient mouse embryonic fibroblasts promotes mitochondrial DNA glycation Free Radic. Biol. Med. 52: 1744-1749.