Abstract
Cortisol is synthesized in the adrenal cortex in response to adrenocorticotropin (ACTH) signaling from cholesterol via a series of reactions that are catalyzed by members of the cytochrome P450 superfamily and hydroxysteroid dehydrogenases. Both the first and last steps of cortisol biosynthesis occur in mitochondria. Based on our previous findings demonstrating that activation of the ACTH signaling cascade changes the ratio of NAD(P)+:NAD(P)H in adrenocortical cells, we hypothesized that these changes in pyridine nucleotide concentrations may regulate the activity of the mitochondrial NAD+‐dependent SIRT deacetylases. We show that both P450scc (side chain cleavage enzyme) and P450 11β hydroxylase are acetylated in mitochondria of H295R human adrenocortical cells. Stimulation with ACTH or dibutyryl cAMP increased the levels of acetylated P450scc and P450 11β, whereas activating SIRT activity using resveratrol decreased P450 acetylation. Resveratrol also increased P450scc and P450 11β protein expression, indicating that acetylation may modulate protein stability. These studies identify a role for NAD+‐dependent SIRT deacetylases in regulating the expression of mitochondrial steroidogenic P450s.
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