title: Induction of androgen formation in the male by a TAT-VDAC1 fusion peptide blocking 14-3-3ɛ protein adaptor and mitochondrial VDAC1 interactions.
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.
authors.affiliation: 1] The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada [2] Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Yasaman
authors.initials: Y
authors.lastname: Aghazadeh
authors.affiliation: 1] The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada [2] Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Martinez-Arguelles
authors.affiliation: 1] The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada [2] Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Jinjiang
authors.initials: J
authors.lastname: Fan
authors.affiliation: 1] The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada [2] Department of Medicine, McGill University, Montreal, Quebec, Canada [3] Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
authors.forename: Martine
authors.initials: M
authors.lastname: Culty
authors.affiliation: 1] The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada [2] Department of Medicine, McGill University, Montreal, Quebec, Canada [3] Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada [4] Department of Biochemistry, McGill University, Montreal, Quebec, Canada [5] Department of Pathology, McGill University, Montreal, Quebec, Canada.
authors.forename: Vassilios
authors.initials: V
authors.lastname: Papadopoulos
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism*; D000728:Androgens / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D007986:Luteinizing Hormone / Q000378:metabolism; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D008958:Models, Molecular; D010455:Peptides / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D021381:Protein Transport; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D013256:Steroids / Q000096:biosynthesis; D013737:Testis / Q000187:drug effects / Q000378:metabolism; D050995:Voltage-Dependent Anion Channel 1 / Q000737:chemistry / Q000378:metabolism*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000737:chemistry*
chemical_list: D048948:14-3-3 Proteins; D000728:Androgens; D010455:Peptides; D011993:Recombinant Fusion Proteins; D013256:Steroids; D054322:tat Gene Products, Human Immunodeficiency Virus; D007986:Luteinizing Hormone; D050995:Voltage-Dependent Anion Channel 1