title: 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.
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.
authors.affiliation: CNS Drug Discovery Unit, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi 2, Fujisawa, Kanagawa, 251-8555, Japan, takeshi.hioki@takeda.com.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hioki
authors.forename: Shunya
authors.initials: S
authors.lastname: Suzuki
authors.forename: Megumi
authors.initials: M
authors.lastname: Morimoto
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Masaki
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Tozawa
authors.forename: Shigeru
authors.initials: S
authors.lastname: Morita
authors.forename: Takashi
authors.initials: T
authors.lastname: Horiguchi
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D001921:Brain / Q000502:physiology; D002540:Cerebral Cortex / Q000502:physiology*; D045303:Cytochromes b / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism; D050259:Genes, Mitochondrial / Q000235:genetics*; D006624:Hippocampus / Q000502:physiology*; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D009252:NADPH Dehydrogenase / Q000235:genetics / Q000378:metabolism; D009919:Orchiectomy; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D051381:Rats; D017207:Rats, Sprague-Dawley; D013739:Testosterone / Q000172:deficiency* / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D014157:Transcription Factors; D013739:Testosterone; D045303:Cytochromes b; D009252:NADPH Dehydrogenase; D003576:Electron Transport Complex IV