Distinctive properties of adrenal cortex mitochondria.
The mitochondria in cells that synthesize steroid hormones not only have enzymes not present in mitochondria of non-steroidogenic cells but also have unique mechanisms for regulating the steroid substrate availability for certain of these enzymes. We have considered in detail the cytochrome P-450scc system that is located in the inner mitochondrial membrane and that catalyzes the initial and rate-determining step in the steroid hormone biosynthetic pathway. The flux through this pathway is regulated both by the levels of these catalysts themselves and by the availability of the substrate cholesterol for conversion to pregnenolone. These two levels of regulation occur in different time frames but are both controlled externally by the action of tissue-specific peptide hormone. We have used the adrenal cortex fasciculata cells as our paradigmatic cell type. The overall picture seems closely similar for mitochondria in other such steroidogenic cells when analogous data are available. Thus, in adrenal cortex fasciculata cells ACTH triggers several long-term (trophic) and short-term (acute) effects upon and within mitochondria that influence the initial and rate-determining step in the steroid hormone biosynthetic pathway. The only second messenger for both effects characterized thus far is cAMP. An increase in membrane-associated cAMP rapidly activates cAMP-dependent protein kinase, which in turn phosphorylates several cellular proteins, e.g., cholesterol ester hydrolase (vide supra). The trophic action, i.e., that produced by exposure of the cells to increased levels of ACTH or cAMP for a prolonged period (minutes to hours), increases the amounts of the steroid hormone synthesizing proteins in the mitochondria by increasing the transcription of the relevant nuclear genes. This latter process is not needed for the acute increase in the rate of steroid hormone biosynthesis. Whether induction of steroidogenic enzymes requires activation of a kinase has not been determined. However, the postulated SHIP proteins provide a mechanism by which cAMP levels and protein synthesis itself may regulate this induction. Mitochondria in steroidogenic tissues exert control over this process by their ability to recognize, import and process correctly the nuclear encoded precursors of the steroidogenic enzymes. Whether control at this level is ultimately dictated by nuclear or mitochondrial gene products or by an interplay between them is still unknown.(ABSTRACT TRUNCATED AT 400 WORDS)
Orme-Johnson
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Department of Biochemistry, Tufts University Health Sciences Campus, Boston, MA 02108.
D000302:Adrenal Cortex / Q000378:metabolism* / Q000648:ultrastructure; D000324:Adrenocorticotropic Hormone / Q000502:physiology; D000818:Animals; D001692:Biological Transport; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D005938:Glucocorticoids / Q000096:biosynthesis; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013256:Steroids / Q000096:biosynthesis*
D005938:Glucocorticoids; D013256:Steroids; D000324:Adrenocorticotropic Hormone; D002786:Cholesterol Side-Chain Cleavage Enzyme