ESPE Yearbook of Paediatric Endocrinology

Brief summary: Genome-wide small hairpin RNA screening revealed a specialized role for the protein phospholipase D6 (PLD6) located at and highly expressed in the outer mitochondrial membrane of cells in steroidogenic organs. Here PLD6 promotes the entrance of LDL/LDLR complex into the mitochondria where LDL-carried cholesterol is released for steroid hormone biosynthesis.Thereby the mitochondrial redox-sensitive CISD2 protein was found to support the trafficking of the LDL/LDLR complex from the cell membrane to the mitochondria.

Cholesterol is the essential and only substrate for initiating steroidogenesis in steroid-producing organs, including the adrenals, gonads and placenta. The first and rate-limiting step for all steroid hormone production takes place in the mitochondrium where the side-chain cleavage enzyme machinery turns cholesterol over to pregnenolone. Thus cholesterol supply plays a pivotal role. In endocrinology, disorders that affect cholesterol supply to this first step of steroidogenesis are well-known and include steroidogenic acute regulatory protein (STAR) deficiency and Smith Lemli Opitz syndrome (DHCR7), which are both causes of adrenal insufficiency and/or differences of sex development. While STAR deficiency has been shown to affect cholesterol transport to the inner mitochondrial membrane, DHCR7 mutations affect enzyme activity of 3β-hydroxysterol-Δ7 reductase which catalyzes the last reaction in cholesterol biosynthesis.

It is thought that about 20% of cholesterol import is STAR independent in the adrenals and gonads. Thus it is conceivable that variants in genes involved in the newly described CISD2 and PLD6 dependent LDL/LDLR transport pathway could also lead to adrenal and gonadal steroid disorders. Additional hints supporting this hypothesis this are: a) mutations in LDLR in humans and mice have been reported to decrease steroid hormone production, b) patients with abetalipoproteinemia who lack circulating LDL have deficient acute cortisol production, c) Pld6-deficient mice are infertile, and d) Cisd2-deficient mice have low testosterone levels and testicular atrophy.