StarD4-mediated translocation of 7-hydroperoxycholesterol to isolated mitochondria: deleterious effects and implications for steroidogenesis under oxidative stress conditions.
StAR family proteins, including StarD4, play a key role in steroidogenesis by transporting cholesterol (Ch) into mitochondria for conversion to pregnenolone. Using a model system consisting of peroxidized cholesterol (7 alpha-OOH)-containing liposomes as donors, we showed that human recombinant StarD4 accelerates 7 alpha-OOH transfer to isolated liver mitochondria, and to a greater extent than Ch transfer. StarD4 had no effect on transfer of non-oxidized or peroxidized phosphatidylcholine, consistent with sterol ring specificity. StarD4-accelerated 7 alpha-OOH transfer to mitochondria resulted in greater susceptibility to free radical lipid peroxidation and loss of membrane potential than in a non-StarD4 control. The novel implication of these findings is that in oxidative stress states, inappropriate StAR-mediated trafficking of peroxidized Ch in steroidogenic tissues could result in damage and dysfunction selectively targeted to mitochondria.
Korytowski
Witold
W
Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Rodriguez-Agudo
Daniel
D
Pilat
Anna
A
Girotti
Albert W
AW
D000818:Animals; D001692:Biological Transport; D002458:Cell Fractionation; D002784:Cholesterol / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D015227:Lipid Peroxidation; D053078:Membrane Potential, Mitochondrial; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008930:Mitochondria, Liver / Q000378:metabolism*; D018384:Oxidative Stress; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
D026901:Membrane Transport Proteins; D011994:Recombinant Proteins; C456544:STARD4 protein, human; C041011:cholesterol 7-hydroperoxide; D002784:Cholesterol