Faculty Collaboration Database

Anti-steroidogenic effects of cholesterol hydroperoxide trafficking in MA-10 Leydig cells: Role of mitochondrial lipid peroxidation and inhibition thereof by selenoperoxidase GPx4. Biochem Biophys Res Commun 2022 Feb 05;591:82-87

Date

01/10/2022

Pubmed ID

34999258

DOI

10.1016/j.bbrc.2021.12.117

Scopus ID

2-s2.0-85122320045 (requires institutional sign-in at Scopus site)   7 Citations

Abstract

Steroid hormone synthesis in steroidogenic cells requires cholesterol (Ch) delivery to/into mitochondria via StAR family trafficking proteins. In previous work, we discovered that 7-OOH, an oxidative stress-induced cholesterol hydroperoxide, can be co-trafficked with Ch, thereby causing mitochondrial redox damage/dysfunction. We now report that exposing MA-10 Leydig cells to Ch/7-OOH-containing liposomes (SUVs) results in (i) a progressive increase in fluorescence probe-detected lipid peroxidation in mitochondrial membranes, (ii) a reciprocal decrease in immunoassay-detected progesterone generation, and ultimately (iii) loss of cell viability with increasing 7-OOH concentration. No significant effects were observed with a phospholipid hydroperoxide over the same concentration range. Glutathione peroxidase GPx4, which can catalyze lipid hydroperoxide detoxification, was detected in mitochondria of MA-10 cells. Mitochondrial lipid peroxidation and progesterone shortfall were exacerbated when MA-10 cells were treated with Ch/7-OOH in the presence of RSL3, a GPx4 inhibitor. However, Ebselen, a selenoperoxidase mimetic, substantially reduced RSL3's negative effects, thereby partially rescuing the cells from peroxidative damage. These findings demonstrate that co-trafficking of oxidative stress-induced 7-OOH can disable steroidogenesis, and that GPx4 can significantly protect against this.

Author List

Pabisz P, Bazak J, Girotti AW, Korytowski W

Author

Albert Girotti PhD, MS Emeritus Professor in the Biochemistry department at Medical College of Wisconsin

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

Animals
Carbolines
Cell Death
Cell Line, Tumor
Cholesterol
Fluorescence
Isoindoles
Leydig Cells
Lipid Peroxidation
Male
Mice
Mitochondria
Mitochondrial Membranes
Organoselenium Compounds
Phosphatidylcholines
Progesterone
Protective Agents
Steroids