Cholesterol hydroperoxide trafficking to macrophage mitochondria and its implications for atherogenesis under oxidative stress

Under oxidative stress (chronic inflammation, obesity), scavenger receptor-expressing macrophages in arterial subendothelial space internalize oxidized LDL (oxLDL) in unregulated fashion, potentially giving rise to foam cells. OxLDL contains cholesterol oxides such as 7-peroxide (7-OOH), alcohol (7-OH), and ketone (7=O). 7-OOH generates 7-OH and 7=O via free radical-mediated turnover, so 7-OH/7=O levels far exceed those of 7-OOH. To limit adverse buildup of cholesterol and its oxides, macrophages export these lipids to HDL and other acceptors via reverse cholesterol transport (RCT). StarD1 on the outer mitochondrial (Mito) membrane participates in cholesterol transport into Mito for conversion to 27-hydroxycholesterol (27-OH) by Cyp27A1 hydroxylase. The 27-OH then signals for plasma membrane ABCA1/G1 transporter expression and cholesterol efflux. Up to now little attention has been directed to potentially more dangerous 7-OOH (vs. 7-OH and 7=O). Using human THP-1 macrophages, we found that 7-OOH could be StarD1-delivered into Mito along with cholesterol. Upon delivery, 7-OOH triggered free radical-mediated lipid peroxidation, which depolarized the Mito membrane and damaged Cyp27A1, reducing 27-OH output and impairing RCT.