Intracellular Dissemination of Peroxidative Stress

Kriska, Tamás; Levchenko, Vladislav; Korytowski, Witold; Atshaves, Barbara P.; Schroeder, Friedhelm; Girotti, Albert W.

doi:10.1074/jbc.m600744200

Cited by 34 publications

(6 citation statements)

References 53 publications

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“…Using unilamellar liposomes as [ 14 C]7α-OOH donors and isolated liver mitochondria as acceptors, we found that SCP-2 accelerated peroxide uptake and that this stimulated both chain peroxidation and loss of mitochondrial membrane potential [38]. Subsequent work showed that a transfect clone of hepatoma cells expressing ~10-fold more SCP-2 than a vector control was much more sensitive to 7α-OOH-induced mitochondrial damage and lethality than the control [39,40]. 7α-OH (an SCP-2 ligand, but redox-inactive) and tert -butyl hydroperoxide (redox-active, but not a ligand) showed no such effects.…”

Section: Cholesterol Hydroperoxide Translocation and Traffickingmentioning

confidence: 99%

Cholesterol Hydroperoxide Generation, Translocation, and Reductive Turnover in Biological Systems

Girotti

Korytowski

2017

Cell Biochem Biophys

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Cholesterol (Ch) is like other unsaturated lipids in being susceptible to peroxidative degradation upon exposure to strong oxidants like hydroxyl radical or peroxynitrite generated under conditions of oxidative stress. In the eukaryotic cell plasma membrane, where most of the cellular Ch resides, peroxidation leads to membrane structural and functional damage from which pathological states may arise. In lipoprotein LDL, Ch and phospholipid peroxidation has long been associated with atherogenesis. Among the many intermediates/products of Ch oxidation, hydroperoxide species (ChOOHs) have a number of different fates and deserve special attention. These fates include (a) damage-enhancement via iron-catalyzed one-electron reduction, (b) damage containment via two-electron reduction, and (c) inter-membrane, inter-lipoprotein, and membrane-lipoprotein translocation, which allows dissemination of one-electron damage or off-site suppression thereof depending on antioxidant location and capacity. In addition, ChOOHs can serve as reliable and conveniently detected mechanistic reporters of free radical- versus non-radical (e.g. singlet oxygen)-mediated reactions. Iron-stimulated peroxidation of Ch and other lipids underlies a newly discovered form of regulated cell death called ferroptosis. These and other deleterious consequences of radical-mediated lipid peroxidation will be discussed in this review.

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Section: Cholesterol Hydroperoxide Translocation and Traffickingmentioning

confidence: 99%

Cholesterol Hydroperoxide Generation, Translocation, and Reductive Turnover in Biological Systems

Girotti

Korytowski

2017

Cell Biochem Biophys

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“…As we know, inhibition of SCP2 increases cell viability in GPX4 -/fibroblasts or RSL3-treated breast cancer cells, but the mechanism driving this remains obscure [24,25,27]. Since SCP2 is a carrier protein that can carry a variety of lipids (including lipid hydroperoxides), the elevation of SCP2 was likely related to the transport of LPO in OA chondrocytes [21][22][23].…”

Section: Discussionmentioning

confidence: 99%

SCP2 mediates the transport of lipid hydroperoxides to mitochondria in chondrocyte ferroptosis

et al. 2023

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Sterol carrier protein 2 (SCP2) is highly expressed in human osteoarthritis (OA) cartilage, accompanied by ferroptosis hallmarks, especially the accumulation of lipid hydroperoxides (LPO). However, the role of SCP2 in chondrocyte ferroptosis remains unexplored. Here, we identify that SCP2 transports cytoplasmic LPO to mitochondria in RSL3-induced chondrocyte ferroptosis, resulting in mitochondrial membrane damage and release of reactive oxygen species (ROS). The localization of SCP2 on mitochondria is associated with mitochondrial membrane potential, but independent of microtubules transport or voltage-dependent anion channel. Moreover, SCP2 promotes lysosomal LPO increase and lysosomal membrane damage through elevating ROS. However, SCP2 is not directly involved in the cell membrane rupture caused by RSL3. Inhibition of SCP2 markedly protects mitochondria and reduces LPO levels, attenuating chondrocyte ferroptosis in vitro and alleviating the progression of OA in rats. Our study demonstrates that SCP2 mediates the transport of cytoplasmic LPO to mitochondria and the spread of intracellular LPO, accelerating chondrocyte ferroptosis.

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“…Although it is beyond the scope of this study to examine the various other physiological functions attributed to SCP2, it is noteworthy that cells overexpressing SCP2 become more susceptible to damage/toxicity by 7␣-OOH, a free radical generated by cholesterol hydroperoxides, because cellular SCP2 binds and traffics 7␣-OOH to mitochondria, where it exerts cellular toxicity (25). Whether reduction in SCP2-mediated cytotoxicity underlies the observed reduction in plaque necrosis remains to be established.…”

Section: Scp2 Deficiency Is Atheroprotectivementioning

confidence: 99%

Sterol carrier protein-2 deficiency attenuates diet-induced dyslipidemia and atherosclerosis in mice

He¹,

Wang²,

Yannie³

et al. 2018

Journal of Biological Chemistry

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Intracellular cholesterol transport proteins move cholesterol to different subcellular compartments and thereby regulate its final metabolic fate. In hepatocytes, for example, delivery of high-density lipoprotein (HDL)-associated cholesterol for bile acid synthesis or secretion into bile facilitates cholesterol elimination from the body (anti-atherogenic effect), whereas delivery for esterification and subsequent incorporation into apolipoprotein B-containing atherogenic lipoproteins ( very-low-density lipoprotein (VLDL)) enhances cholesterol secretion into the systemic circulation (pro-atherogenic effect). Intracellular cholesterol transport proteins such as sterol carrier protein-2 (SCP2) should, therefore, play a role in regulating these pro- or anti-atherosclerotic processes. Here, we sought to evaluate the effects of SCP2 deficiency on the development of diet-induced atherosclerosis. We generated LDLR mice deficient in SCP2/SCPx (LS) and examined the effects of this deficiency on Western diet-induced atherosclerosis. SCP2/SCPx deficiency attenuated atherosclerosis in LS mice by >80% and significantly reduced plasma cholesterol and triglyceride levels. Investigation of the likely underlying mechanisms revealed a significant reduction in intestinal cholesterol absorption (given as an oral gavage) in SCP2/SCPx-deficient mice. Consistently, siRNA-mediated knockdown of SCP2 in intestinal cells significantly reduced cholesterol uptake. Furthermore, hepatic triglyceride/VLDL secretion from the liver or hepatocytes isolated from SCP2/SCPx-deficient mice was significantly reduced. These results indicate an important regulatory role for SCP2 deficiency in attenuating diet-induced atherosclerosis by limiting intestinal cholesterol absorption and decreasing hepatic triglyceride/VLDL secretion. These findings suggest targeted inhibition of SCP2 as a potential therapeutic strategy to reduce Western diet-induced dyslipidemia and atherosclerosis.

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Intracellular Dissemination of Peroxidative Stress

Cited by 34 publications

References 53 publications

Cholesterol Hydroperoxide Generation, Translocation, and Reductive Turnover in Biological Systems

Cholesterol Hydroperoxide Generation, Translocation, and Reductive Turnover in Biological Systems

SCP2 mediates the transport of lipid hydroperoxides to mitochondria in chondrocyte ferroptosis

Sterol carrier protein-2 deficiency attenuates diet-induced dyslipidemia and atherosclerosis in mice

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