Adrenocorticotropin‐Stimulated Phosphorylation of RhoA Facilitates Binding to mDia1, Mitochondrial Trafficking, and Cortisol Biosynthesis

Abstract

Steroid hormones are formed by several successive enzymatic transformations of the substrate cholesterol in the mitochondria and endoplasmic reticulum (ER). In the human adrenal cortex, the peptide hormone adrenocorticotropin (ACTH) directs cortisol and andrenal biosynthesis by activating a cAMP/cAMP‐dependent protein kinase (PKA) pathway. In this study, we used the H295R human adrenocortical cell line to show that ACTH and Bt2cAMP increase mitochondrial movement. Agents that alter the polymerization of tubulin attenuate both mitochondrial movement and cortisol biosynthesis. The interaction between RhoA, one of member of the Rho family of small GTPases and one of its effectors, mDia1 regulate ACTH/cAMP‐stimulated mitochondrial trafficking and cortisol production. Phosphorylation of RhoA in response to ACTH increased the binding of RhoA to mDia and facilitated both mitochondrial movement and cortisol secretion. We conclude that this increase in organelle trafficking facilitates cortisol production by bring mitochondria and ER in close proximity for efficient transfer of substrate.