New insights into signal transduction pathways in adrenal steroidogenesis: role of mitochondrial fusion, lipid mediators, and MAPK phosphatases

Abstract

Hormone-receptor signal transduction has been extensively studied in adrenal gland. Zona glomerulosa and fasciculata cells are responsible for glucocorticoid and mineralocorticoid synthesis by adrenocorticotropin (ACTH) and angiotensin II (Ang II) stimulation, respectively. Since the rate-limiting step in steroidogenesis occurs in the mitochondria, these organelles are key players in the process. The maintenance of functional mitochondria depends on mitochondrial dynamics, which involves at least two opposite events, i.e., mitochondrial fusion and fission. This review presents state-of-the-art data on the role of mitochondrial fusion proteins, such as mitofusin 2 (Mfn2) and optic atrophy 1 (OPA1), in Ang II-stimulated steroidogenesis in adrenocortical cells. Both proteins are upregulated by Ang II, and Mfn2 is strictly necessary for adrenal steroid synthesis. The signaling cascades of steroidogenic hormones involve an increase in several lipidic metabolites such as arachidonic acid (AA). In turn, AA metabolization renders several eicosanoids released to the extracellular medium able to bind membrane receptors. This report discusses OXER1, an oxoeicosanoid receptor which has recently arisen as a novel participant in adrenocortical hormone-stimulated steroidogenesis through its activation by AA-derived 5-oxo-ETE. This work also intends to broaden knowledge of phospho/dephosphorylation relevance in adrenocortical cells, particularly MAP kinase phosphatases (MKPs) role in steroidogenesis. At least three MKPs participate in steroid production and processes such as the cellular cycle, either directly or by means of MAP kinase regulation. To sum up, this review discusses the emerging role of mitochondrial fusion proteins, OXER1 and MKPs in the regulation of steroid synthesis in adrenal cortex cells.

Keywords: MKP-3; OXER1; adrenocortical cells; mitochondrial fusion; mitofusin 2; oxoeicosanoids; protein kinases; steroidogenesis.

Figure 1

Scheme of the signal transduction pathways triggered by Ang II and OXER1 in adrenocortical cells. Ang II interacts with the AT1R and promotes the activity of PLC which leads to the activation of members of the PKC superfamily, particularly PKCα, ε and δ. Ang II favors the increase in Mfn2 expression, driving mitochondrial fusion. This event enables mitochondrial activation of MEK and ERK and proper localization of StAR, to achieve full steroid production. In line, Drp1 decreases in mitochondria, leaning the balance toward mitochondrial fusion. Through an ACSL4/AA- dependent mechanism, Ang II promotes an increase in oxoeicosanoids. These compounds may activate, in an autocrine and paracrine way, OXER1 on the cell membrane. Signal transduction involves ERK1/2 and p38 phosphorylation dependent on PKCε and δ, and a further increase in StAR expression, steroid synthesis, and cell migration. Simultaneously, activated AT1R by Ang II leads to ERK and FOXO1 phosphorylation and an increase in MKP-3 levels. Later, MKP-3 dephosphorylates p-ERK and p-FOXO1 to promote FOXO1 nuclear translocation and its subsequent activation of p21 protein expression. Dashed and solid arrows indicate indirect and direct activation, respectively.