Obesity and hepatosteatosis in mice with enhanced oxidative DNA damage processing in mitochondria

Haihong Zhang, Chenghui Xie, Horace J. Spencer, Chunlai Zuo, Masahiro Higuchi, Gouri Ranganathan, Philip A. Kern, Ming W. Chou, Qin Huang, Bartosz Szczesny, Sankar Mitra, Amanda J. Watson, Geoffrey P. Margison, Chun Yang Fan

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Mitochondria play critical roles in oxidative phosphorylation and energy metabolism. Increasing evidence supports that mitochondrial DNA (mtDNA) damage and dysfunction play vital roles in the development of many mitochondria-related diseases, such as obesity, diabetes mellitus, infertility, neurodegenerative disorders, and malignant tumors in humans. Human 8-oxoguanine-DNA glycosylase 1 (hOGG1) transgenic (TG) mice were produced by nuclear microinjection. Transgene integration was analyzed by PCR. Transgene expression was measured by RT-PCR and Western blot analysis. Mitochondrial DNA damage was analyzed by mutational analyses and measurement of mtDNA copy number. Total fat content was measured by a whole-body scan using dual-energy X-ray absorptiometry. The hOGG1 overexpression in mitochondria increased the abundance of intracellular free radicals and major deletions in mtDNA. Obesity in hOGG1 TG mice resulted from increased fat content in tissues, produced by hyperphagia. The molecular mechanisms of obesity involved overexpression of genes in the central orexigenic (appetite-stimulating) pathway, peripheral lipogenesis, down-regulation of genes in the central anorexigenic (appetite-suppressing) pathway, peripheral adaptive thermogenesis, and fatty acid oxidation. Diffuse hepatosteatosis, female infertility, and increased frequency of malignant lymphoma were also seen in these hOGG1 TG mice. High levels of hOGG1 expression in mitochondria, resulting in enhanced oxidative DNA damage processing, may be an important factor in human metabolic syndrome, infertility, and malignancy.

Original languageEnglish (US)
Pages (from-to)1715-1727
Number of pages13
JournalAmerican Journal of Pathology
Volume178
Issue number4
DOIs
StatePublished - Apr 2011

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Zhang, H., Xie, C., Spencer, H. J., Zuo, C., Higuchi, M., Ranganathan, G., Kern, P. A., Chou, M. W., Huang, Q., Szczesny, B., Mitra, S., Watson, A. J., Margison, G. P., & Fan, C. Y. (2011). Obesity and hepatosteatosis in mice with enhanced oxidative DNA damage processing in mitochondria. American Journal of Pathology, 178(4), 1715-1727. https://doi.org/10.1016/j.ajpath.2010.12.038