madman
Super Moderator
Abstract
Late-onset hypogonadism, resulting from a deficiency in serum testosterone (T), affects the health and quality of life of millions of aging men. T is synthesized by Leydig cells (LCs) in response to luteinizing hormone (LH). LH binds LC plasma membrane receptors, inducing the formation of a supramolecular complex of cytosolic and mitochondrial proteins, the Steroidogenic InteracTomE (SITE). SITE proteins are involved in targeting cholesterol to CYP11A1 in the mitochondria, the first enzyme of the steroidogenic cascade. Cholesterol translocation is the rate-determining step in T formation. With aging, LC defects occur that include changes in SITE, an increasingly oxidative intracellular environment, and reduced androgen formation and serum T levels. T replacement therapy (TRT) will restore T levels, but reported side effects make it desirable to develop additional strategies for increasing T. One approach is to target LC protein-protein interactions and thus increase T production by the hypofunctional Leydig cells themselves.
1. Introduction: Testosterone production and the aging testis
2. Cell biology of Leydig cell steroidogenesis
3. Steroidogenic cholesterol: Sources, trafficking and targeting to CYP11A1
4. SITE proteins in cholesterol import machinery and steroidogenesis
4.1. ACBD1/DBI
4.2. TSPO (18-kDa)
4.3. VDAC
4.4. STAR
4.5. 14-3-3 proteins
4.6. Other proteins of SITE
5. Oxidant/antioxidant imbalance and reductions in testosterone production
6. Existing treatments to increase serum T levels
7. Targeting critical protein-protein interactions to reverse LOH
8. Conclusions and future directions
LOH resulting from an age-dependent deficiency in serum T affects the quality of life and well-being of millions of aging men worldwide via its association with numerous chronic and other diseases. Understanding the molecular determinants of LOH would allow us to identify new therapeutic targets that could be used to restore the ability of the testis to form T and to design preventive approaches to maintain T formation. The discovery of specialized protein networks forming the SITE, a hormonally regulated multiprotein complex that drives the transfer of cholesterol from storage sites across membranes and aqueous spaces into the IMM, is a new way of looking at complex processes. Understanding the differences in the organization and regulation of the SITE in old versus young LCs should explain differences in the ability of these cells to form T. Moreover, it is now clear that, despite their perceived similarities, the aging adrenal and testis present critical differences in the regulation of their respective steroidogenic pathways that may be key for developing tissue-specific therapies. These tissue-specific differences also indicate that the age-dependent decline in T by LCs is not simply a general phenomenon associated with aging that is common to all steroidogenic and other tissues. Identifying LC-specific and age-dependent PPIs is expected to provide targets for drug development to restore T formation without affecting adrenal corticosteroid production. Moreover, by understanding cause-effect relationships between oxidative stress and steroid formation, we will better understand the cause(s) of reduced T formation with aging, and this might lead to interventions designed to extend years of healthy life.
Exploiting these differences is a new concept that should lead to testis-specific treatments for LOH.
In addition to providing potential benefit to aging men, the design of new therapies that increase intratesticular bioactive androgen levels without affecting the hypothalamic-pituitary axis could be of importance for subfertile and infertile young men, including the many men diagnosed with idiopathic infertility who present with reduced circulating T, men with orchitis, and men following trauma [injury to genitalia, spinal cord injury], torsion, surgery, chemotherapy, irradiation, and in response to some medications (acquired hypogonadism).
Late-onset hypogonadism, resulting from a deficiency in serum testosterone (T), affects the health and quality of life of millions of aging men. T is synthesized by Leydig cells (LCs) in response to luteinizing hormone (LH). LH binds LC plasma membrane receptors, inducing the formation of a supramolecular complex of cytosolic and mitochondrial proteins, the Steroidogenic InteracTomE (SITE). SITE proteins are involved in targeting cholesterol to CYP11A1 in the mitochondria, the first enzyme of the steroidogenic cascade. Cholesterol translocation is the rate-determining step in T formation. With aging, LC defects occur that include changes in SITE, an increasingly oxidative intracellular environment, and reduced androgen formation and serum T levels. T replacement therapy (TRT) will restore T levels, but reported side effects make it desirable to develop additional strategies for increasing T. One approach is to target LC protein-protein interactions and thus increase T production by the hypofunctional Leydig cells themselves.
1. Introduction: Testosterone production and the aging testis
2. Cell biology of Leydig cell steroidogenesis
3. Steroidogenic cholesterol: Sources, trafficking and targeting to CYP11A1
4. SITE proteins in cholesterol import machinery and steroidogenesis
4.1. ACBD1/DBI
4.2. TSPO (18-kDa)
4.3. VDAC
4.4. STAR
4.5. 14-3-3 proteins
4.6. Other proteins of SITE
5. Oxidant/antioxidant imbalance and reductions in testosterone production
6. Existing treatments to increase serum T levels
7. Targeting critical protein-protein interactions to reverse LOH
8. Conclusions and future directions
LOH resulting from an age-dependent deficiency in serum T affects the quality of life and well-being of millions of aging men worldwide via its association with numerous chronic and other diseases. Understanding the molecular determinants of LOH would allow us to identify new therapeutic targets that could be used to restore the ability of the testis to form T and to design preventive approaches to maintain T formation. The discovery of specialized protein networks forming the SITE, a hormonally regulated multiprotein complex that drives the transfer of cholesterol from storage sites across membranes and aqueous spaces into the IMM, is a new way of looking at complex processes. Understanding the differences in the organization and regulation of the SITE in old versus young LCs should explain differences in the ability of these cells to form T. Moreover, it is now clear that, despite their perceived similarities, the aging adrenal and testis present critical differences in the regulation of their respective steroidogenic pathways that may be key for developing tissue-specific therapies. These tissue-specific differences also indicate that the age-dependent decline in T by LCs is not simply a general phenomenon associated with aging that is common to all steroidogenic and other tissues. Identifying LC-specific and age-dependent PPIs is expected to provide targets for drug development to restore T formation without affecting adrenal corticosteroid production. Moreover, by understanding cause-effect relationships between oxidative stress and steroid formation, we will better understand the cause(s) of reduced T formation with aging, and this might lead to interventions designed to extend years of healthy life.
Exploiting these differences is a new concept that should lead to testis-specific treatments for LOH.
In addition to providing potential benefit to aging men, the design of new therapies that increase intratesticular bioactive androgen levels without affecting the hypothalamic-pituitary axis could be of importance for subfertile and infertile young men, including the many men diagnosed with idiopathic infertility who present with reduced circulating T, men with orchitis, and men following trauma [injury to genitalia, spinal cord injury], torsion, surgery, chemotherapy, irradiation, and in response to some medications (acquired hypogonadism).
