Evolutionary origin of the mitochondrial cholesterol transport machinery reveals a universal mechanism of steroid hormone biosynthesis in animals.

Jinjiang Fan,Vassilios Papadopoulos,Wei Yan

doi:10.1371/journal.pone.0076701

Jinjiang Fan, Vassilios Papadopoulos + Show 1 more

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https://doi.org/10.1371/journal.pone.0076701

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Journal: PloS one	Publication Date: Oct 4, 2013
Citations: 41	License type: CC BY 4.0

Affiliation: McGill University Health Centre, McGill University

Abstract

Steroidogenesis begins with the transport of cholesterol from intracellular stores into mitochondria via a series of protein-protein interactions involving cytosolic and mitochondrial proteins located at both the outer and inner mitochondrial membranes. In adrenal glands and gonads, this process is accelerated by hormones, leading to the production of high levels of steroids that control tissue development and function. A hormone-induced multiprotein complex, the transduceosome, was recently identified, and is composed of cytosolic and outer mitochondrial membrane proteins that control the rate of cholesterol entry into the outer mitochondrial membrane. More recent studies unveiled the steroidogenic metabolon, a bioactive, multimeric protein complex that spans the outer-inner mitochondrial membranes and is responsible for hormone-induced import, segregation, targeting, and metabolism of cholesterol by cytochrome P450 family 11 subfamily A polypeptide 1 (CYP11A1) in the inner mitochondrial membrane. The availability of genome information allowed us to systematically explore the evolutionary origin of the proteins involved in the mitochondrial cholesterol transport machinery (transduceosome, steroidogenic metabolon, and signaling proteins), trace the original archetype, and predict their biological functions by molecular phylogenetic and functional divergence analyses, protein homology modeling and molecular docking. Although most members of these complexes have a history of gene duplication and functional divergence during evolution, phylogenomic analysis revealed that all vertebrates have the same functional complex members, suggesting a common mechanism in the first step of steroidogenesis. An archetype of the complex was found in invertebrates. The data presented herein suggest that the cholesterol transport machinery is responsible for steroidogenesis among all vertebrates and is evolutionarily conserved throughout the entire animal kingdom.

Highlights

The rate-limiting step in steroid biosynthesis is the transport of the sole substrate cholesterol from intracellular stores into mitochondria where cholesterol is metabolized by the inner mitochondrial membrane enzyme cytochrome P450 family 11 subfamily A polypeptide 1 (CYP11A1) to pregnenolone, which is the precursor of adrenal, gonadal, placental, and brain steroids [1]
A series of proteins essential for steroid hormone formation (Figure 1A), including the mitochondrial translocator protein (18kDa; TSPO), cytosolic steroidogenic acute regulatory protein (STAR) or START domain-containing 1 (STARD1), acyl-coenzyme A binding domain-containing 3 (ACBD3, protein kinaseassociated protein 7 (PAP7)), a protein interacting directly with TSPO, acyl-coenzyme A binding domaincontaining 1 (ACBD1) or diazepam-binding inhibitor (DBI), an endogenous TSPO ligand, and cAMP-dependent protein kinase regulatory type I alpha (PRKAR1A), which is critical for the phosphorylation for STARD1 to induce STARD1 activity, in part, at the outer mitochondrial membrane [2,3,4,5]
Identification of the homologous cholesterol transport members involved in the steroidogenesis machinery using the basic local alignment search tool (BLAST)

Summary

Introduction

The rate-limiting step in steroid biosynthesis is the transport of the sole substrate cholesterol from intracellular stores into mitochondria where cholesterol is metabolized by the inner mitochondrial membrane enzyme cytochrome P450 family 11 subfamily A polypeptide 1 (CYP11A1) to pregnenolone, which is the precursor of adrenal, gonadal, placental, and brain steroids [1]. In adrenal glands and gonads, cholesterol transfer into mitochondria is accelerated by hormones and cAMP, leading to the production of high levels of steroids that reach all tissues and cells of the body through circulation. These steroids control multiple body functions during the lifespan of the organism. A series of proteins essential for steroid hormone formation (Figure 1A), including the mitochondrial translocator protein (18kDa; TSPO), cytosolic steroidogenic acute regulatory protein (STAR) or START domain-containing 1 (STARD1), acyl-coenzyme A binding domain-containing 3 (ACBD3, PAP7), a protein interacting directly with TSPO, acyl-coenzyme A binding domaincontaining 1 (ACBD1) or diazepam-binding inhibitor (DBI), an endogenous TSPO ligand, and cAMP-dependent protein kinase regulatory type I alpha (PRKAR1A), which is critical for the phosphorylation for STARD1 to induce STARD1 activity, in part, at the outer mitochondrial membrane [2,3,4,5]

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Conclusion