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

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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 14-3-3ε protein adaptor as a negative regulator of steroidogenesis. Steroidogenesis begins in mitochondria. 14-3-3ε 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 14-3-3ε site of interaction with VDAC1 blocked 14-3-3ε-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 GnRH antagonist, which dampened LH and T production.

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Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study.

Carol A Derby, John B. McKinlay, William J Bremner … (2002)

We used longitudinal data from the Massachusetts Male Aging Study, a large population-based random-sample cohort of men aged 40-70 yr at baseline, to establish normative age trends for serum level of T and related hormones in middle-aged men and to test whether general health status affected the age trends. Of 1,709 men enrolled in 1987-1989, 1,156 were followed up 7-10 yr afterward. By repeated-measures statistical analysis, we estimated simultaneously the cross-sectional age trend of each hormone between subjects within the baseline data, the cross-sectional trend between subjects within the follow-up data, and the longitudinal trend within subjects between baseline and follow-up. Total T declined cross-sectionally at 0.8%/yr of age within the follow-up data, whereas both free and albumin-bound T declined at about 2%/yr, all significantly more steeply than within the baseline data. Sex hormone-binding globulin increased cross-sectionally at 1.6%/yr in the follow-up data, similarly to baseline. The longitudinal decline within subjects between baseline and follow-up was considerably steeper than the cross-sectional trend within measurement times for total T (1.6%/yr) and bioavailable T (2-3%/yr). Dehydroepiandrosterone, dehydroepiandrosterone sulfate, cortisol, and estrone showed significant longitudinal declines, whereas dihydrotestosterone, pituitary gonadotropins, and PRL rose longitudinally. Apparent good health, defined as absence of chronic illness, prescription medication, obesity, or excessive drinking, added 10-15% to the level of several androgens and attenuated the cross-sectional trends in T and LH but did not otherwise affect longitudinal or cross-sectional trends. The paradoxical finding that longitudinal age trends were steeper than cross-sectional trends suggests that incident poor health may accelerate the age-related decline in androgen levels.

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The structural basis for 14-3-3:phosphopeptide binding specificity.

Michael Yaffe, Katrin Rittinger, Stefano Volinia … (1997)

The 14-3-3 family of proteins mediates signal transduction by binding to phosphoserine-containing proteins. Using phosphoserine-oriented peptide libraries to probe all mammalian and yeast 14-3-3s, we identified two different binding motifs, RSXpSXP and RXY/FXpSXP, present in nearly all known 14-3-3 binding proteins. The crystal structure of 14-3-3zeta complexed with the phosphoserine motif in polyoma middle-T was determined to 2.6 A resolution. The bound peptide is in an extended conformation, with a tight turn created by the pS +2 Pro in a cis conformation. Sites of peptide-protein interaction in the complex rationalize the peptide library results. Finally, we show that the 14-3-3 dimer binds tightly to single molecules containing tandem repeats of phosphoserine motifs, implicating bidentate association as a signaling mechanism with molecules such as Raf, BAD, and Cbl.

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Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels.

Rebecca Vigen (2013)

Rates of testosterone therapy are increasing and the effects of testosterone therapy on cardiovascular outcomes and mortality are unknown. A recent randomized clinical trial of testosterone therapy in men with a high prevalence of cardiovascular diseases was stopped prematurely due to adverse cardiovascular events raising concerns about testosterone therapy safety. To assess the association between testosterone therapy and all-cause mortality, myocardial infarction (MI), or stroke among male veterans and to determine whether this association is modified by underlying coronary artery disease. A retrospective national cohort study of men with low testosterone levels (<300 ng/dL) who underwent coronary angiography in the Veterans Affairs (VA) system between 2005 and 2011. Primary outcome was a composite of all-cause mortality, MI, and ischemic stroke. Of the 8709 men with a total testosterone level lower than 300 ng/dL, 1223 patients started testosterone therapy after a median of 531 days following coronary angiography. Of the 1710 outcome events, 748 men died, 443 had MIs, and 519 had strokes. Of 7486 patients not receiving testosterone therapy, 681 died, 420 had MIs, and 486 had strokes. Among 1223 patients receiving testosterone therapy, 67 died, 23 had MIs, and 33 had strokes. At 3 years after coronary angiography, the Kaplan-Meier estimated cumulative percentages with events were 19.9%in the no testosterone therapy group vs 25.7%in the testosterone therapy group,with an absolute risk difference of 5.8%(95%CI, -1.4%to 13.1%) [corrected].The Kaplan-Meier estimated cumulative percentages with events among the no testosterone therapy group vs testosterone therapy group at 1 year after coronary angiography were 10.1% vs 11.3%; at 2 years, 15.4% vs 18.5%; and at 3 years, 19.9% vs 25.7 [corrected].There was no significant difference in the effect size of testosterone therapy among those with and without coronary artery disease (test for interaction, P = .41). Among a cohort of men in the VA health care system who underwent coronary angiography and had a low serum testosterone level, the use of testosterone therapy was associated with increased risk of adverse outcomes. These findings may inform the discussion about the potential risks of testosterone therapy.

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Author and article information

Journal

Journal ID (nlm-journal-id): 100890581

Journal ID (pubmed-jr-id): 21793

Journal ID (nlm-ta): Mol Ther

Journal ID (iso-abbrev): Mol. Ther.

Title: Molecular therapy : the journal of the American Society of Gene Therapy

ISSN (Print): 1525-0016

ISSN (Electronic): 1525-0024

Publication date Nihms-submitted: 18 June 2014

Publication date (Electronic): 20 June 2014

Publication date (Print): October 2014

Publication date PMC-release: 02 June 2015

Volume: 22

Issue: 10

Pages: 1779-1791

Affiliations

[1 ]The Research Institute of the McGill University Health Centre and the Department of Medicine, McGill University, 1650 Cedar Avenue, Montreal, Quebec, H3G 1A4, Canada

[2 ]Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, H3G 1A4, Canada

[3 ]Departments of Biochemistry and Pathology, McGill University, Montreal, Quebec, H3G 1A4, Canada

Author notes

Correspondence should be addressed to V. Papadopoulos, The Research Institute of the McGill University Health Center, Montreal General Hospital, 1650 Cedar Avenue, C10-148, Montreal, Quebec H3G 1A4, Canada. Tel: 514-934-1934 ext. 44580; Fax: 514-934-8439; vassilios.papadopoulos@ 123456mcgill.ca

Article

Manuscript ID: CAMS4498

DOI: 10.1038/mt.2014.116

PMC ID: 4428399

PubMed ID: 24947306

SO-VID: 83d73d8d-4711-4b92-9f13-fc388b3f1d19

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

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Most cited references 43

Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study.

The structural basis for 14-3-3:phosphopeptide binding specificity.

Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels.

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