Trafficking of oxidative stress-generated lipid hydroperoxides: pathophysiological implications

Abstract

Lipid hydroperoxides (LOOHs) are reactive intermediates that arise during peroxidation of unsaturated phospholipids, glycolipids and cholesterol in biological membranes and lipoproteins. Non-physiological lipid peroxidation (LPO) typically occurs under oxidative stress conditions associated with pathologies such as atherogenesis, neurodegeneration, and carcinogenesis. As key intermediates in the LPO process, LOOHs are susceptible to one-electron versus two-electron reductive turnover, the former exacerbating membrane or lipoprotein damage/dysfunction and the latter diminishing it. A third possible LOOH fate is translocation to an acceptor membrane/lipoprotein, where one- or two-electron reduction may then ensue. In the case of cholesterol (Ch)-derived hydroperoxides (ChOOHs), translocation can be specifically stimulated by StAR family trafficking proteins, which are normally involved in Ch homeostasis and Ch-mediated steroidogenesis. In this review, we discuss how these processes can be impaired by StAR-mediated ChOOH and Ch co-trafficking to mitochondria of vascular macrophages and steroidogenic cells, respectively. The protective effects of endogenous selenoperoxidase, GPx4, are also discussed. This is the first known example of detrimental ChOOH transfer via a natural Ch trafficking pathway and inhibition thereof by GPx4.

Keywords:

• Steroidogenesis
• mitochondria
• ChOOH transfer-damage
• GPx4

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The authors’ research was supported by the following awards: USPHS Grant CA70832 and Rock River Pilot Grant FP14689 (to AWG), National Institutes of Health and Polish National Science Center Grants 2014/13/B/NZ3/00833 and 2017/26/M/NZ3/01232 (to WK).