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Cited by 43Hormonal and reproductive studiesSperm and Testicular Function14-3-3 protein interactions

Induction of Androgen Formation in the Male by a TAT-VDAC1 Fusion Peptide Blocking 14-3-3ɛ Protein Adaptor and Mitochondrial VDAC1 Interactions

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Aghazadeh, Yasaman, Martinez-Arguelles, Daniel B, Fan, Jinjiang, Culty, Martine, Papadopoulos, Vassilios·2014·Molecular Therapy
DOI 10.1038/mt.2014.116PMC PMC4428399
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Abstract

Low testosterone (T), a major cause of male hypogonadism and infertility, is linked to mood changes, fatigue, osteoporosis, reduced bone-mass index, and aging. The treatment of choice, T replacement therapy, has been linked with increased risk for prostate cancer and luteinizing hormone (LH) suppression, and shown to lead to infertility, cardiovascular diseases, and obesity. Alternate methods to induce T with lower side effects are desirable. In search of the mechanisms regulating T synthesis in the testes, we identified the 14-3-3ɛ protein adaptor as a negative regulator of steroidogenesis. Steroidogenesis begins in mitochondria. 14-3-3ɛ interacts with the outer mitochondrial membrane voltage-dependent anion channel (VDAC1) protein, forming a scaffold that limits the availability of cholesterol for steroidogenesis. We report the development of a tool able to induce endogenous T formation. Peptides able to penetrate testes conjugated to 14-3-3ɛ site of interaction with VDAC1 blocked 14-3-3ɛ-VDAC1 interactions while at the same time increased VDAC1-translocator protein (18 kDa) interactions that induced steroid formation in rat testes, leading to increased serum T levels. These peptides rescued intratesticular and serum T formation in adult male rats treated with gonadotropin-releasing hormone antagonist, which dampened LH and T production.

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  • Functional partners of the transduceosome include mitochondria-associated members of the 14-3-3 adaptor protein family and kinase signalers such as ERK1/2.

    “In addition, functional partners of the transduceosome have been identified, including mitochondria-associated members of the 14-3-3 adaptor protein family (92, 93) as well as kinase signalers such as extracellular signal-regulated kinase (ERK) 1/2 (94);”

    From Adrenal Mitochondria and Steroidogenesis: From Individual Proteins to Functional Protein Assemblies (2016) · cites this paper as [93]

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Authors
Aghazadeh, Y., Martinez-Arguelles, D. B., Fan, J., Culty, M., & Papadopoulos, V.
Affiliations
Research Institute of the McGill University Health Centre (CA)
Corresponding author
Papadopoulos, Vassilios
ORCID
Venue
Molecular Therapy
Publisher
Elsevier BV
Published
2014-10
Volume
22
Issue
10
Pages
1779-1791
ISSN
1525-0016 (ISSN-L)
DOI
10.1038/mt.2014.116
PMC
PMC4428399
OpenAlex
W2002257803
Cited by
43
References
10
Citations by year
2025: 4 · 2024: 3 · 2023: 4 · 2022: 4 · 2021: 5 · 2020: 2 · 2019: 7 · 2018: 4 · 2017: 3 · 2016: 2 · 2015: 4 · 2014: 1
FWCI
2.68
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Therapy (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Brown University
  • Canadian Institutes of Health Research (87265_1, 125983, 125983_1, 102647_1, MOP102647)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
  • Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › 14-3-3 protein interactions
Keywords
testosterone production, steroidogenesis, 14-3-3ε, VDAC1, mitochondrial voltage-dependent anion channel, translocator protein (TSPO), peptide fusion, male hypogonadism, testis, LH suppression, GnRH antagonist, male infertility, testosterone replacement therapy
MeSH terms
Androgens, Animals, Cell Line, Luteinizing Hormone, Male, Mitochondria, Models, Molecular, Peptides, Protein Binding, Protein Conformation, Recombinant Fusion Proteins, Steroids, Testis, Protein Transport, 14-3-3 Proteins, Voltage-Dependent Anion Channel 1, Mice, Rats, tat Gene Products, Human Immunodeficiency Virus

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