Intertwined regulators: hypoxia pathway proteins, microRNAs, and phosphodiesterases in the control of steroidogenesis

Abstract

Oxygen sensing is of paramount importance for maintaining cellular and systemic homeostasis. In response to diminished oxygen levels, the hypoxia-inducible factors (HIFs) orchestrate various biological processes. These pivotal transcription factors have been identified as key regulators of several biological events. Notably, extensive research from our group and others has demonstrated that HIF1α exerts an inverse regulatory effect on steroidogenesis, leading to the suppression of crucial steroidogenic enzyme expression and a subsequent decrease in steroid levels. These steroid hormones occupy pivotal roles in governing a myriad of physiological processes. Substantial or prolonged fluctuations in steroid levels carry detrimental consequences across multiple organ systems and underlie various pathological conditions, including metabolic and immune disorders. MicroRNAs serve as potent mediators of multifaceted gene regulatory mechanisms, acting as influential epigenetic regulators that modulate a broad spectrum of gene expressions. Concomitantly, phosphodiesterases (PDEs) play a crucial role in governing signal transduction. PDEs meticulously manage intracellular levels of both cAMP and cGMP, along with their respective signaling pathways and downstream targets. Intriguingly, an intricate interplay seems to exist between hypoxia signaling, microRNAs, and PDEs in the regulation of steroidogenesis. This review highlights recent advances in our understanding of the role of microRNAs during hypoxia-driven processes, including steroidogenesis, as well as the possibilities that exist in the application of HIF prolyl hydroxylase (PHD) inhibitors for the modulation of steroidogenesis.

Keywords: Hypoxia; MicroRNA; Phosphodiesterases; Regulation; Steroidogenesis.

Fig. 1

Hypoxia signaling pathway. Under normal oxygen levels (normoxia), hypoxia-inducible factor (HIF)-α subunits are hydroxylated by HIF prolyl hydroxylase domain proteins (PHDs). PHDs require oxygen (O₂), ferrous iron (Fe²⁺), and 2-oxoglutarate (2-OG) for their activity. Hydroxylated HIFs are recognized and bound by the von Hippel-Lindau tumor suppressor protein (VHL). VHL recruits components of the E3-ubiquitin ligase complex and facilitates the ubiquitination and proteasomal degradation of hydroxylated HIFs. HIF is also regulated in a VHL-independent manner by the activity of factor inhibiting HIF1 (FIH), an asparaginyl hydroxylase. The conserved asparaginyl (Asn) residue within the C-terminal activation domain in HIFα is hydroxylated under normoxia or mild hypoxia, thereby suppressing HIF transcriptional activity by preventing interaction with the transcriptional coactivators p300/CBP. Conversely, under conditions of relatively low oxygen levels (hypoxia), PHD activity and the degradation of HIFα subunits as well as FIH activity are inhibited. Therefore, HIFα subunits are stabilized and are able to dimerize with the HIFβ subunit. In the nucleus, active HIFα/β dimer in complex with other cofactors promote the transcription of target genes with hypoxia response elements (HREs) such as transferrin (Tf), erythropoietin (Epo), numerous microRNAs, and other genes involved in metabolism, angiogenesis, erythropoiesis, steroidogenesis, and other hypoxia regulated processes

Fig. 2

Hypoxia pathway proteins-microRNA-phosphodiesterase crosstalk in steroidogenesis regulation. Hypoxia regulates steroid production through either direct binding of HIFs to the HREs in the promoter of steroidogenic enzymes or by a crosstalk of HIFs with other regulators such as microRNAs (miRNAs) and phosphodiesterases (PDE) (see further). The expression and activity of steroidogenic enzymes as well as steroidogenesis are regulated by miRNAs and PDE. MiRNAs and PDE are also regulated by each other, which ultimately impacts steroidogenesis either positively or negatively. MiRNAs may also target Hif1α. Hypoxia is able to alter the expression and activity of miRNAs and PDE, which ultimately affects steroid production