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Macrophage mitochondrial damage from StAR transport of 7‐hydroperoxycholesterol: Implications for oxidative stress‐impaired reverse cholesterol transport
Author(s) -
Korytowski Witold,
Wawak Katarzyna,
Pabisz Pawel,
Schmitt Jared C.,
Girotti Albert W.
Publication year - 2014
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2013.10.051
Subject(s) - mitochondrion , oxidative stress , abca1 , reverse cholesterol transport , cholesterol , microbiology and biotechnology , chemistry , stimulation , depolarization , inner mitochondrial membrane , oxidative phosphorylation , gene knockdown , mitochondrial ros , downregulation and upregulation , biology , biochemistry , endocrinology , transporter , apoptosis , lipoprotein , gene
StAR family proteins in vascular macrophages participate in reverse cholesterol transport (RCT). We hypothesize that under pathophysiological oxidative stress, StARs will transport not only cholesterol to macrophage mitochondria, but also pro‐oxidant cholesterol hydroperoxides (7‐OOHs), thereby impairing early‐stage RCT. Upon stimulation with dibutyryl‐cAMP, RAW264.7 macrophages exhibited a strong time‐dependent induction of mitochondrial StarD1 and plasma membrane ABCA1, which exports cholesterol. 7α‐OOH uptake by stimulated RAW cell mitochondria (like cholesterol uptake) was strongly reduced by StarD1 knockdown, consistent with StarD1 involvement. Upon uptake by mitochondria, 7α‐OOH (but not redox‐inactive 7α‐OH) triggered lipid peroxidation and membrane depolarization while reducing ABCA1 upregulation. These findings provide strong initial support for our hypothesis.