Faculty Collaboration Database

Deleterious cholesterol hydroperoxide trafficking in steroidogenic acute regulatory (StAR) protein-expressing MA-10 Leydig cells: implications for oxidative stress-impaired steroidogenesis. J Biol Chem 2013 Apr 19;288(16):11509-19

Date

03/08/2013

Pubmed ID

23467407

Pubmed Central ID

PMC3630865

DOI

10.1074/jbc.M113.452151

Scopus ID

2-s2.0-84876590564 (requires institutional sign-in at Scopus site)   33 Citations

Abstract

Steroidogenic acute regulatory (StAR) proteins in steroidogenic cells are implicated in the delivery of cholesterol (Ch) from internal or external sources to mitochondria (Mito) for initiation of steroid hormone synthesis. In this study, we tested the hypothesis that under oxidative stress, StAR-mediated trafficking of redox-active cholesterol hydroperoxides (ChOOHs) can result in site-specific Mito damage and dysfunction. Steroidogenic stimulation of mouse MA-10 Leydig cells with dibutyryl-cAMP (Bt2cAMP) resulted in strong expression of StarD1 and StarD4 proteins over insignificant levels in nonstimulated controls. During incubation with the ChOOH 3β-hydroxycholest-5-ene-7α-hydroperoxide (7α-OOH) in liposomes, stimulated cells took up substantially more hydroperoxide in Mito than controls, with a resulting loss of membrane potential (ΔΨm) and ability to drive progesterone synthesis. 7α-OOH uptake and ΔΨm loss were greatly reduced by StarD1 knockdown, thus establishing the role of this protein in 7α-OOH delivery. Moreover, 7α-OOH was substantially more toxic to stimulated than nonstimulated cells, the former dying mainly by apoptosis and the latter dying by necrosis. Importantly, tert-butyl hydroperoxide, which is not a StAR protein ligand, was equally toxic to stimulated and nonstimulated cells. These findings support the notion that like Ch itself, 7α-OOH can be transported to/into Mito of steroidogenic cells by StAR proteins and therein induce free radical damage, which compromises steroid hormone synthesis.

Author List

Korytowski W, Pilat A, Schmitt JC, Girotti AW

Author

Albert W. Girotti PhD Adjunct Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Biological Transport, Active
Cell Line
Cholesterol
Gene Expression Regulation
Gonadal Steroid Hormones
Leydig Cells
Male
Membrane Potential, Mitochondrial
Mice
Mitochondria
Mutagens
Phosphoproteins