Nigericin inhibits accumulation of the steroidogenic acute regulatory protein but not steroidogenesis.
The steroidogenic acute regulatory (StAR) protein mediates the delivery of cholesterol from the outer to the inner mitochondrial membrane, where the cholesterol side chain cleavage complex converts it to pregnenolone. While the mechanism by which this mitochondrial protein acts is poorly understood, one component of the mitochondrial electrochemical gradient, the electrochemical potential (DeltaPsi), appears to be essential. In this study, the importance of the other component, the proton gradient (DeltapH), was examined. Disruption of DeltapH with the electroneutral K(+)/H(+) exchanger, nigericin, had no effect on steroidogenesis in MA-10 mouse Leydig tumor cells at concentrations which significantly reduced StAR protein levels. These data indicate for the first time in true steroidogenic cells, that StAR can act prior to being fully imported into the mitochondria and are consistent with observations made in COS-1 cells using mutant forms of StAR. These results support the hypothesis that a DeltaPsi-dependent factor is required for StAR activity and demonstrate that nigericin is the first compound described, capable of inhibiting StAR accumulation without affecting steroidogenesis.
King
S R
SR
Department of Cell Biology and Biochemistry, Texas Technical University Health Sciences Center, 3601 4th Street, 79430, Lubbock, TX, USA.
Walsh
L P
LP
Stocco
D M
DM
D000818:Animals; D004563:Electrochemistry; D006863:Hydrogen-Ion Concentration; D007476:Ionophores / Q000494:pharmacology; D007984:Leydig Cell Tumor / Q000235:genetics / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009550:Nigericin / Q000494:pharmacology*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D013256:Steroids / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured; D000098682:Steroidogenic Acute Regulatory Protein
D007476:Ionophores; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D013256:Steroids; D000098682:Steroidogenic Acute Regulatory Protein; D009550:Nigericin