Role of mitochondria in steroidogenesis.

All steroids are made from cholesterol by a complex array of enzymes that includes cytochrome P450 enzymes in both the mitochondria and endoplasmic reticulum. The structures and mechanisms of catalysis by the mitochondrial and endoplasmic reticulum P450s are very similar, but their electron transport mechanisms differ. Nevertheless, mitochondrial P450scc is inactive when targeted to the endoplasmic reticulum with its electron-transfer partners. Adrenals and gonads receive cholesterol from low-density lipoproteins, store it as cholesterol esters, and transport cholesterol to mitochondria by ill-defined mechanisms. The acute quantitative regulation of steroidogenesis is determined by cholesterol import into mitochondria by the steroidogenic acute regulatory protein(StAR). The chronic regulation, determining net steroidogenic capacity, is determined by the amount of P450scc protein present, which is determined by gene transcription. Mutations in StAR cause congenital lipoid adrenal hyperplasia (lipoid CAH), characterized by absent steroidogenesis, potentially lethal salt loss, 46, XY sex reversal and massively enlarged adrenals engorged with cholesterol esters.Non-classic lipoid CAH is a newly described variant caused by StAR mutations that retain 10-25% of function, and characterized by onset of glucocorticoid deficiency after 2 years of age, and mild defects in mineralocorticoid and sex steroid synthesis. Rare mutations in P450scc result in both classic and non-classic hormonal syndromes that are indistinguishable from lipoid CAH, but have small adrenals.