Induction Of Androgen Formation By A Tat-vdac1 Fusion Peptide

[Michael Scally MD]

Aghazadeh Y, Martinez-Arguelles DB, Fan J, Culty M, Papadopoulos V. Induction of Androgen Formation in the Male by a TAT-VDAC1 Fusion Peptide Blocking 14-3-3varepsilon Protein Adaptor and Mitochondrial VDAC1 Interactions. Mol Ther 2014;22(10):1779-91. http://www.nature.com/mt/journal/v22/n10/full/mt2014116a.html

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 14-3-3varepsilon protein adaptor as a negative regulator of steroidogenesis.

Steroidogenesis begins in mitochondria. 14-3-3varepsilon 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 14-3-3varepsilon site of interaction with VDAC1 blocked 14-3-3varepsilon-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.

 

[Michael Scally MD]

Optimization of TSPO-VDAC1 Binding and Mitochondrial Steroidogenesis via The Fusion Peptide TVS167
(a) The molecular cooperation among the steroidogenic acute regulatory program (STAR), the voltage-dependent anion channel 1 (VDAC1), and the 18-kDa translocator protein (TSPO) is core to the transduceosome complex and drives steroidogenesis.
(b) During hormone stimulation, the mitochondrial recruitment of 14-3-3e prevents the functional interaction between VDAC1 and TSPO, thereby perturbing steroidogenesis.
(c) TAT-VDAC1 Ser167 (TVS167) prevents the interaction between 14-3-3e and VDAC1, facilitating TSPO-VDAC1 binding and steroidogenesis.
ANT, adenine nucleotide translocase;
IMM, inner mitochondrial membrane;
OMM, outer mitochondrial membrane.


Campanella M. Peptide Targeting of Mitochondria Elicits Testosterone Formation. Mol Ther 2014;22(10):1727-9. http://www.nature.com/mt/journal/v22/n10/full/mt2014171a.html

Testosterone (T) is the principal sex hormone responsible for growth and development of the reproductive system in male vertebrates. It has historically received much attention not only from the medical and scientific communities but also from the general public, owing to its psychological and behavioral effects.

T drives the asymmetry of several biological processes spanning virilization to anabolism, disease prevention, and aging. In this issue of Molecular Therapy, Aghazadeh et al. describe a novel fusion peptide, TVS167, that can induce T formation in rat testes and increase its serum level as well as rescue its synthesis in adult male rats exposed to antagonists of the gonadotropin-releasing hormone, which constitutes the initial step in the hypothalamic–pituitary–gonadal axis governing T production. http://www.nature.com/mt/journal/v22/n10/full/mt2014116a.html

This peptide acts by exploiting the interaction between the voltage-dependent anion channel 1 (VDAC1) and the 18-kDa translocator protein (TSPO) within the mitochondrial transduceosome, a multicomponent molecular machine that controls lipid import and steroidogenesis.

 

[Michael Scally MD]

Aghazadeh Y, Zirkin BR, Papadopoulos V. Pharmacological regulation of the cholesterol transport machinery in steroidogenic cells of the testis. Vitam Horm. 2015;98:189-227. https://www.sciencedirect.com/science/article/pii/S0083672914000193

Reduced serum testosterone (T), or hypogonadism, is estimated to affect about 5 million American men, including both aging and young men. Low serum T has been linked to mood changes, worsening cognition, fatigue, depression, decreased lean body mass and bone mineral density, increased visceral fat, metabolic syndrome, decreased libido, and sexual dysfunction.

Administering exogenous T, known as T-replacement therapy (TRT), reverses many of the symptoms of low T levels. However, this treatment can result in luteinizing hormone suppression which, in turn, can lead to reduced sperm numbers and infertility, making TRT inappropriate for men who wish to father children.

Additionally, TRT may result in supraphysiologic T levels, skin irritation, and T transfer to others upon contact; and there may be increased risk of prostate cancer and cardiovascular disease, particularly in aging men. Therefore, the development of alternate therapies for treating hypogonadism would be highly desirable.

To do so requires greater understanding of the series of steps leading to T formation and how they are regulated, and the identification of key steps that are amenable to pharmacological modulation so as to induce T production. We review herein our current understanding of mechanisms underlying the pharmacological induction of T formation in hypogonadal testis.

 

[Michael Scally MD]

Highlights
· Historical perspective on pharmacological targeting of TSPO in steroidogenesis.
· Targeting mitochondrial transduceosome for control of steroidogenesis.
· Review of recent genetic engineering work targeting transduceosome components.

Papadopoulos V, Aghazadeh Y, Fan J, Campioli E, Zirkin B, et al. Translocator protein-mediated pharmacology of cholesterol transport and steroidogenesis. Mol Cell Endocrinol. https://www.sciencedirect.com/science/article/pii/S0303720715001458

Steroidogenesis begins with cholesterol transfer into mitochondria through the transduceosome, a complex composed of cytosolic proteins that include steroidogenesis acute regulatory protein (STAR), 14-3-3 adaptor proteins, and the outer mitochondrial membrane proteins Translocator Protein (TSPO) and Voltage-Dependent Anion Channel (VDAC).

TSPO is a drug- and cholesterol- binding protein found at particularly high levels in steroid synthesizing cells. Its aberrant expression has been linked to cancer, neurodegeneration, neuropsychiatric disorders and primary hypogonadism.

Brain steroids serve as local regulators of neural development and excitability. Reduced levels of these steroids have been linked to depression, anxiety and neurodegeneration.

Reduced serum testosterone is common among subfertile young men and aging men, and is associated with depression, metabolic syndrome and reduced sexual function. Although testosterone-replacement therapy is available, there are undesired side-effects.

TSPO drug ligands have been proposed as therapeutic agents to regulate steroid levels in the brain and testis.