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Brain Testosterone Deficiency Leads to Down-Regulation of Mitochondrial Gene Expression in Rat Hippocampus Accompanied by a Decline in Peroxisome Proliferator-Activated Receptor-γ Coactivator 1α Expression

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Abstract

Age-related decrease of testosterone levels in blood and brain is believed to be associated with neurodegenerative diseases such as Alzheimer’s disease. However, the effect of testosterone on brain function is not well understood. Therefore, we investigated the impact of testosterone deprivation on mitochondrial gene expression in the brain of male gonadectomized (GDX) rats. We found that peripheral castration led to testosterone deficiency in the brain and caused a significant reduction in protein and mRNA expression of genes encoded by mitochondrial DNA, namely NADPH dehydrogenase subunit 1, subunit 4, cytochrome b, and cytochrome c oxidase subunit 1 and subunit 3 in the hippocampus. In addition, gene expression of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), which is a master regulator of mitochondrial biogenesis, and its downstream transcriptional factors, nuclear respiratory factors 1 and 2 and mitochondrial transcription factors A and B2, were also decreased in the hippocampus of GDX rats. These reductions in the expression of mitochondrial gene and transcriptional coactivators and factors were recovered by androgen replacement. These findings indicate that androgen plays an important role in mitochondrial gene expression in the hippocampus.

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Acknowledgements

We would like to thank Richard Urquhart, MD for helpful comments on this manuscript. We thank Drs. Keisuke Hirai, Hideaki Nagaya, Takeo Wada, Shinichi Kondou, Yasushi Shintani, Hideki Matsui, Kaori Ishikawa, Prof. Kazuhide Inoue, and Associate Profs. Takao Shimazoe, Motohiro Nishida, and Makoto Tsuda (Kyushu University, Fukuoka, Japan) for their helpful discussions. We also thank Akira Matsubara for her technical assistance.

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The authors declare no conflict of interest.

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Authors and Affiliations

  1. CNS Drug Discovery Unit, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi 2, Fujisawa, Kanagawa, 251-8555, Japan

    Takeshi Hioki, Shunya Suzuki & Shigeru Morita

  2. Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi 2, Fujisawa, Kanagawa, 251-8555, Japan

    Megumi Morimoto & Tsuneo Masaki

  3. Cardiovascular and Metabolic Drug Discovery Unit, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi 2, Fujisawa, Kanagawa, 251-8555, Japan

    Ryuichi Tozawa

  4. Bio-Molecular Research Laboratory, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi 2, Fujisawa, Kanagawa, 251-8555, Japan

    Takashi Horiguchi

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  1. Takeshi Hioki
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  2. Shunya Suzuki
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  3. Megumi Morimoto
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Correspondence to Takeshi Hioki.

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Hioki, T., Suzuki, S., Morimoto, M. et al. Brain Testosterone Deficiency Leads to Down-Regulation of Mitochondrial Gene Expression in Rat Hippocampus Accompanied by a Decline in Peroxisome Proliferator-Activated Receptor-γ Coactivator 1α Expression. J Mol Neurosci 52, 531–537 (2014). https://doi.org/10.1007/s12031-013-0108-3

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