| Background. Mitochondria play important roles in cellular energy metabolism, production of reactive oxygen species (ROS), and regulation of apoptosis. ROS can cause oxidative damage to DNA. One of the most common oxidation products of mitochondrial DNA (mtDNA) is 8-oxoguanine (8-oxoG), which can mispair with A, yielding a G: C to A: T transversion if not sufficiently repaired. 8-oxoguanine DNA glycosylase (OGG1) can specifically remove 8-oxo-G lesion from DNA through the base excision repair (BER) pathway. BER is a tightly coordinated system involving enzymatic activity of several repair proteins (glycosylase, AP endonuclease, polymerase, and ligase). Overexpression of individual BER proteins can cause an imbalance in BER, leading to paradoxically increased DNA damage. Designs and methods. To investigate the biological effects of the hOGG1 gene, we generated hOGG1 overexpression models both in vitro and in vivo by targeting hOGG1 2a cDNA expression to the mitochondria of a human hepatoma cell line, HepG2, and transgenic (TG) mice. Results . Both in vitro cell culture and in vivo TG mouse studies showed that overexpression of hOGG1 in the mitochondria caused more mtDNA damage, aberrantly more active mitochondrial respiration, and increased production of ROS. As a result, HepG2 cells overexpressing hOGG1 underwent more apoptosis and became more sensitive to the chemotherapeutic agent, cisplatin while TG mice overexpressing hOGG1 developed obesity, female infertility, and B-cell malignant lymphoma. The obesity phenotype seen in these hOGG1 TG mice was due to increased food intake as a result of leptinergic blockage, increased lipogenesis, decreased fatty acid oxidation, and adaptive thermogenesis. Conclusions. Overexpression of a single BER enzyme, hOGG1, in the mitochondria is detrimental, resulting in enhanced cytotoxic effects and apoptosis in cancer cells and a variety of adverse biological consequences in TG mice. Our results are significant to the future development of novel, more effective anticancer therapies and in improved insights into the complex molecular mechanisms by which obesity develops. |
