An Outer Mitochondrial Translocase, Tom22, Is Crucial for Inner Mitochondrial Steroidogenic Regulation in Adrenal and Gonadal Tissues

Author:

Rajapaksha Maheshinie1,Kaur Jasmeet1,Prasad Manoj1,Pawlak Kevin J.1,Marshall Brendan2,Perry Elizabeth W.2,Whittal Randy M.3,Bose Himangshu S.14

Affiliation:

1. Department of Biochemistry, Mercer University School of Medicine, Savannah, Georgia, USA

2. Department of Cellular Biology and Anatomy, Georgia Regents University, Augusta, Georgia, USA

3. Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada

4. Anderson Cancer Institute, Memorial University Medical Center, Savannah, Georgia, USA

Abstract

ABSTRACT After cholesterol is transported into the mitochondria of steroidogenic tissues, the first steroid, pregnenolone, is synthesized in adrenal and gonadal tissues to initiate steroid synthesis by catalyzing the conversion of pregnenolone to progesterone, which is mediated by the inner mitochondrial enzyme 3β-hydroxysteroid dehydrogenase 2 (3βHSD2). We report that the mitochondrial translocase Tom22 is essential for metabolic conversion, as its knockdown by small interfering RNA (siRNA) completely ablated progesterone conversion in both steroidogenic mouse Leydig MA-10 and human adrenal NCI cells. Tom22 forms a 500-kDa complex with mitochondrial proteins associated with 3βHSD2. Although the absence of Tom22 did not inhibit mitochondrial import of cytochrome P450scc (cytochrome P450 side chain cleavage enzyme) and aldosterone synthase, it did inhibit 3βHSD2 expression. Electron microscopy showed that Tom22 is localized at the outer mitochondrial membrane (OMM), while 3βHSD2 is localized at the inner mitochondrial space (IMS), where it interacts through a specific region with Tom22 with its C-terminal amino acids and a small amino acid segment of Tom22 exposed to the IMS. Therefore, Tom22 is a critical regulator of steroidogenesis, and thus, it is essential for mammalian survival.

Funder

HHS | NIH | National Institute of Child Health and Human Development

Publisher

American Society for Microbiology

Subject

Cell Biology,Molecular Biology

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