Major Mitochondrial DNA Deletions in Transgenic Mice Overexpressing a Human 8-Oxoguanine DNA-Glycosylase Leading to High Frequency of Lymphoma and Myeloproliferative Disorder.
Authors: Huang Qin , Zhang Haihong , Chen Wei , Weiss Lawrence M. , Fan Chun-yang 
Published: April 2020

Abstract
Alterations of nuclear genes in human disease or tumors have been well investigated in past several decades and unequivocally established a predominant role in the pathogenesis. However, the relationship of mitochondrial genome alteration or dysfunction and human disease or tumor remains large unknown. Mitochondria are dynamic organelles involved in oxidative phosphorylation and production of reactive oxygen species (ROS). Accumulated evidence supports that mitochondrial DNA damage and dysfunction play vital roles in the development of a wide array of mitochondria-related diseases, such as obesity, diabetes, infertility, neurodegenerative disorders and malignant tumors in human. We previously described the development of a transgenic (TG) mouse model for mitochondrial damage by overexpressing human mitochondrial isoform of 8-oxoguanine DNA Glycosylase 1 (hOGG1) gene (Blood108:A 2246, 2006). The TG mice developed early onset obesity, female infertility, very high frequencies of B-cell lymphomas and human essential thrombocythemia like myeloproliferative disorders. We now reported here that major mitochondrial DNA deletions were frequently identified in a variety of organs in these hOGG1 TG mice and these deletions may largely contribute to the biologic phenotypes of the TG mice. The development and characterization of hOGG1 TG mice have been described previously. In the current study, mitochondrial DNA samples were extracted from various organs and tumor tissues of hOGG1 TG and age-matched non-TG control animals and subjected to PCR analysis using 8 specific primer sets franking the breakpoints of 7 major mitochondrial DNA deletions. Six deletions (3.7, 3.82, 3.86, 4.2, 4.9 and 5.2 kilobase in length) have been previously reported in the literatures. One novel deletion of 15.kilobase was identified in hOGG1 TG mouse in our laboratory. Among 7 major mitochondrial DNA deletion analyzed, Five (3.7, 3.86, 4.2, 5.2 and 15 kilobase in length) deletions were detected in higher frequency in various organs of hOGG1 TG but not in non-TG control mice, suggesting that those deletions might be resulted from overexpression of the transgene hOGG1. Notably, 3 deletions (del3729, del3868, and del15139) were identified in significantly higher in TG mouse spleen with myeloproliferative disorders or TG mouse spleen with diffuse large B-cell lymphoma, in comparison to the spleen of the age-matched wild type animals (P&lt;0.01). Accordingly, protein expression of major mitochondrial complexes were also significantly reduced in hOGG1 TG mice. Furthermore, major mitochondrial DNA deletion due to overexpressed hOGG1 leading to imbalanced mitochondrial DNA base excision repair pathways resulted in defects in mitochondrial respiration and significantly increased in ROS production in those TG mice. We therefore concluded that major mitochondrial DNA deletions with resultant reduced mitochondrial protein expression, mitochondrial dysfunction and increased in ROS production may represent an important molecular mechanism by which these hOGG TG mice develop obesity, infertility and hematologic malignancies.