Induction of androgen formation in the male by a TAT-VDAC1 fusion peptide blocking 14-3-3ɛ protein adaptor and mitochondrial VDAC1 interactions

Mol Ther. 2014 Oct;22(10):1779-91. doi: 10.1038/mt.2014.116. Epub 2014 Jun 20.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 14-3-3 Proteins / metabolism*
  • Androgens / metabolism*
  • Animals
  • Cell Line
  • Luteinizing Hormone / metabolism
  • Male
  • Mice
  • Mitochondria / metabolism*
  • Models, Molecular
  • Peptides / metabolism*
  • Protein Binding
  • Protein Conformation
  • Protein Transport
  • Rats
  • Recombinant Fusion Proteins / administration & dosage
  • Recombinant Fusion Proteins / pharmacology*
  • Steroids / biosynthesis
  • Testis / drug effects
  • Testis / metabolism
  • Voltage-Dependent Anion Channel 1 / chemistry
  • Voltage-Dependent Anion Channel 1 / metabolism*
  • tat Gene Products, Human Immunodeficiency Virus / chemistry*

Substances

  • 14-3-3 Proteins
  • Androgens
  • Peptides
  • Recombinant Fusion Proteins
  • Steroids
  • tat Gene Products, Human Immunodeficiency Virus
  • Luteinizing Hormone
  • Voltage-Dependent Anion Channel 1