Skip to main content

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

Journal of Molecular Neuroscience volume 52, pages 531–537 (2014)Cite this article

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.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price includes VAT (USA)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  • Bonda DJ, Lee HP, Lee HG, Friedlich AL, Perry G, Zhu X, Smith MA (2010a) Novel therapeutics for Alzheimer’s disease: an update. Curr Opin Drug Discov Devel 13:235–246

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bonda DJ, Wang X, Perry G, Nunomura A, Tabaton M, Zhu X, Smith MA (2010b) Oxidative stress in Alzheimer disease: a possibility for prevention. Neuropharmacology 59:290–294

    CAS  PubMed  Article  Google Scholar 

  • Chen JQ, Cammarata PR, Baines CP, Yager JD (2009) Regulation of mitochondrial respiratory chain biogenesis by estrogens/estrogen receptors and physiological, pathological and pharmacological implications. Biochim Biophys Acta 1793:1540–1570

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Chu LW, Tam S, Lee PW, Wong RL, Yik PY, Tsui W, Song Y, Cheung BM, Morley JE, Lam KS (2008) Bioavailable testosterone is associated with a reduced risk of amnestic mild cognitive impairment in older men. Clin Endocrinol 68:589–598

    CAS  Article  Google Scholar 

  • Du J, Ma M, Zhao Q, Fang L, Chang J, Wang Y, Fei R, Song X (2013) Mitochondrial bioenergetic deficits in the hippocampi of rats with chronic ischemia-induced vascular dementia. Neuroscience 231:345–352

    CAS  PubMed  Article  Google Scholar 

  • Evans DA, Funkenstein HH, Albert MS, Scherr PA, Cook NR, Chown MJ, Hebert LE, Hennekens CH, Taylor JO (1989) Prevalence of Alzheimer’s disease in a community population of older persons. Higher than previously reported. JAMA 262:2551–2556

    CAS  PubMed  Article  Google Scholar 

  • Feldman HA, Longcope C, Derby CA, Johannes CB, Araujo AB, Coviello AD, Bremner WJ, McKinlay JB (2002) Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. J Clin Endocrinol Metab 87:589–598

    CAS  PubMed  Article  Google Scholar 

  • Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR, Baltimore Longitudinal Study of Aging (2001) Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab 86:724–731

    CAS  PubMed  Article  Google Scholar 

  • Hirai K, Aliev G, Nunomura A, Fujioka H, Russell RL, Atwood CS, Johnson AB, Kress Y, Vinters HV, Tabaton M, Shimohama S, Cash AD, Siedlak SL, Harris PL, Jones PK, Petersen RB, Perry G, Smith MA (2001) Mitochondrial abnormalities in Alzheimer’s disease. J Neurosci 21:3017–3023

    CAS  PubMed  Google Scholar 

  • Hock MB, Kralli A (2009) Transcriptional control of mitochondrial biogenesis and function. Annu Rev Physiol 71:177–203

    CAS  PubMed  Article  Google Scholar 

  • Hogervorst E, Williams J, Budge M, Barnetson L, Combrinck M, Smith AD (2001) Serum total testosterone is lower in men with Alzheimer’s disease. Neuro Endocrinol Lett 22:163–168

    CAS  PubMed  Google Scholar 

  • Hogervorst E, Combrinck M, Smith AD (2003) Testosterone and gonadotropin levels in men with dementia. Neuro Endocrinol Lett 24:203–208

    CAS  PubMed  Google Scholar 

  • Kemper MF, Zhao Y, Duckles SP, Krause DN (2013) Endogenous ovarian hormones affect mitochondrial efficiency in cerebral endothelium via distinct regulation of PGC-1 isoforms. J Cereb Blood Flow Metab 33:122–128. doi:10.1038/jcbfm.2012.159

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Kish SJ, Bergeron C, Rajput A, Dozic S, Mastrogiacomo F, Chang LJ, Wilson JM, DiStefano LM, Nobrega JN (1992) Brain cytochrome oxidase in Alzheimer’s disease. J Neurochem 59:776–779

    CAS  PubMed  Article  Google Scholar 

  • Kujoth GC, Hiona A, Pugh TD, Someya S, Panzer K, Wohlgemuth SE, Hofer T, Seo AY, Sullivan R, Jobling WA, Morrow JD, Van Remmen H, Sedivy JM, Yamasoba T, Tanokura M, Weindruch R, Leeuwenburgh C, Prolla TA (2005) Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 309:481–484

    CAS  PubMed  Article  Google Scholar 

  • Leuner K, Müller WE, Reichert AS (2012) From mitochondrial dysfunction to amyloid Beta formation: novel insights into the pathogenesis of Alzheimer’s disease. Mol Neurobiol 46:186–193

    CAS  PubMed  Article  Google Scholar 

  • Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443:787–795

    CAS  PubMed  Article  Google Scholar 

  • Lu T, Pan Y, Kao SY, Li C, Kohane I, Chan J, Yankner BA (2004) Gene regulation and DNA damage in the ageing human brain. Nature 429:883–891

    CAS  PubMed  Article  Google Scholar 

  • Mao P, Reddy PH (2011) Aging and amyloid beta-induced oxidative DNA damage and mitochondrial dysfunction in Alzheimer’s disease: implications for early intervention and therapeutics. Biochim Biophys Acta 1812:1359–1370

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Masliah E, Mallory M, Hansen L, DeTeresa R, Alford M, Terry R (1994) Synaptic and neuritic alterations during the progression of Alzheimer’s disease. Neurosci Lett 174:67–72

    CAS  PubMed  Article  Google Scholar 

  • Moffat SD, Zonderman AB, Metter EJ, Blackman MR, Harman SM, Resnick SM (2002) Longitudinal assessment of serum free testosterone concentration predicts memory performance and cognitive status in elderly men. J Clin Endocrinol Metab 87:5001–5007

    CAS  PubMed  Article  Google Scholar 

  • Moffat SD, Zonderman AB, Metter EJ, Kawas C, Blackman MR, Harman SM, Resnick SM (2004) Free testosterone and risk for Alzheimer disease in older men. Neurology 62:188–193

    CAS  PubMed  Article  Google Scholar 

  • Muller M, den Tonkelaar I, Thijssen JH, Grobbee DE, van der Schouw YT (2003) Endogenous sex hormones in men aged 40–80 years. Eur J Endocrinol 149:583–589

    CAS  PubMed  Article  Google Scholar 

  • Mutisya EM, Bowling AC, Beal MF (1994) Cortical cytochrome oxidase activity is reduced in Alzheimer’s disease. J Neurochem 63:2179–2184

    CAS  PubMed  Article  Google Scholar 

  • Puigserver P, Wu Z, Park CW, Graves R, Wright M, Spiegelman BM (1998) A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92:829–839

    CAS  PubMed  Article  Google Scholar 

  • Rocca WA, Amaducci LA, Schoenberg BS (1986) Epidemiology of clinically diagnosed Alzheimer’s disease. Ann Neurol 19:415–424

    CAS  PubMed  Article  Google Scholar 

  • Rodríguez-Cuenca S, Monjo M, Gianotti M, Proenza AM, Roca P (2007) Sex steroid receptor expression profile in brown adipose tissue. Effects of hormonal status. Cell Physiol Biochem 20:877–886

    PubMed  Article  Google Scholar 

  • Rosario ER, Chang L, Head EH, Stanczyk FZ, Pike CJ (2011) Brain levels of sex steroid hormones in men and women during normal aging and in Alzheimer’s disease. Neurobiol Aging 32:604–613

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Seyedreza P, Alireza MN, Seyedebrahim H (2012) Role of testosterone in memory impairment of Alzheimer disease induced by streptozotocin in male rats. Daru 20:98

    PubMed Central  PubMed  Article  Google Scholar 

  • Shiota M, Yokomizo A, Tada Y, Inokuchi J, Tatsugami K, Kuroiwa K, Uchiumi T, Fujimoto N, Seki N, Naito S (2010) Peroxisome proliferator-activated receptor gamma coactivator-1alpha interacts with the androgen receptor (AR) and promotes prostate cancer cell growth by activating the AR. Mol Endocrinol 24:114–127

    CAS  PubMed  Article  Google Scholar 

  • Simpkins JW, Dykens JA (2008) Mitochondrial mechanisms of estrogen neuroprotection. Brain Res Rev 57:421–430

    CAS  PubMed  Article  Google Scholar 

  • Smith MA, Nunomura A, Zhu X, Takeda A, Perry G (2000) Metabolic, metallic, and mitotic sources of oxidative stress in Alzheimer disease. Antioxid Redox Signal 2:413–420

    CAS  PubMed  Article  Google Scholar 

  • Spritzer MD, Daviau ED, Coneeny MK, Engelman SM, Prince WT, Rodriguez-Wisdom KN (2011) Effects of testosterone on spatial learning and memory in adult male rats. Horm Behav 59:484–496

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Wallace DC (1999) Mitochondrial diseases in man and mouse. Science 283:1482–1488

    CAS  PubMed  Article  Google Scholar 

  • Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V, Troy A, Cinti S, Lowell B, Scarpulla RC, Spiegelman BM (1999) Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98:115–124

    CAS  PubMed  Article  Google Scholar 

Download references

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.

Conflicts of interest

The authors declare no conflict of interest.

Author information

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

Authors
  1. Takeshi Hioki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shunya Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Megumi Morimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tsuneo Masaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ryuichi Tozawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shigeru Morita
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Takashi Horiguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Takeshi Hioki.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-013-0108-3

Keywords

  • Aging
  • Neurodegenerative disease
  • Testosterone
  • Mitochondria
  • PGC-1α