Regulation of Leydig cell steroidogenesis: intriguing network of signaling pathways and mitochondrial signalosome

Abstract

© 2019 Elsevier Ltd Leydig cell steroidogenesis is the complex process of biosynthesis of androgens (mainly testosterone)from cholesterol as a precursor, via steroidogenic machinery, which includes cholesterol transporters, steroidogenic enzymes, transcription factors, and wide variety of regulators. In this review, we will summarize important discoveries made over the past several years that have contributed to our current understanding of (1)a complex and intriguing network of plethora signaling pathways regulating Leydig cell steroidogenesis during prenatal and postnatal life, as well as the essential roles played by autocrine and paracrine regulation; (2)the importance of the mitochondrial signalosome, interactome, and dynamics; and (3)the regulation and adaptation of Leydig cell steroidogenesis during psychophysiological stress and aging. It is well known that neural, endocrine, paracrine (including cryptocrine and juxtacrine), and autocrine inputs activate complicated signaling networks targeting Leydig cell steroidogenic machinery. Besides the well-established, leading regulatory role of cAMP-PRKA signaling, which is followed by cGMP-PRKG, mitogen-activated protein kinase, PRKC, AMPK, progenitor adult Leydig cell, and phosphatase signaling, recent data have revealed other signaling pathways (desert hedgehog, nerve growth factor, neuregulin-1, notch, insulin/insulin-like growth factor 1 receptor, retinoic acid, Wnt/β-catenin, and Wilms tumor gene 1)and molecules (14-3-3γ-adapter protein, 14-3-3ε-adapter protein, clock genes, gonadotropin-regulated testicular RNA helicase, LIM-homeobox gene 9, and Smad ubiquitylation regulatory factor 1)as important regulators of Leydig cell steroidogenesis. Recent data have also emphasized the importance of mitochondria-associated membranes, mitochondria–peroxisome interactions, lipophagy/autophagy, and processes of mitochondrial dynamics for Leydig cell steroidogenesis. These processes not only correlate with but also are essential for testosterone production, being dependent on the same regulators. Furthermore, recent discoveries have highlighted that the structural complexity of the testis and interactions between Leydig and neighboring cells are essential for regulation, preservation, and maintenance of Leydig cell steroidogenesis. Because androgens play a crucial role in the masculinization of male fetuses, in secondary male-specific sexual maturation, as well as in the well-being and reproduction of male adults, all recent knowledge may help in the prevention and treatment of androgen-related disorders, both in males and females.