Lipid peroxidation as a possible cause of cataract

doi:10.1016/0047-6374(88)90080-2

Mechanisms of Ageing and Development

Volume 44, Issue 1, July 1988, Pages 69-89

https://doi.org/10.1016/0047-6374(88)90080-2 Get rights and content

Abstract

The role of free-radical-induced lipid oxidation in the development of human lens opacity was studied. Physico-chemical parameters of the lens fiber membranes at different stages of cataract have been investigated. The deterioration of lens fiber plasma membranes structure preceding formation of large aggregates in lenticular matter, leading to lens opacity, was observed by electron microscopy. Initial stages of cataract were characterized by the accumulation of primary (diene conjugates, cetodienes) lipid peroxidation (LPO) products, while in the later stages there was a prevalence of end LPO fluorescent products. Reliable increase in oxiproducts of fatty acyl content of lenticular lipids was shown by direct gas chromatography technique obtaining fatty acid fluorine-substituted derivatives. The lens opacity degree is found to correlate with the level of the end LPO fluorescent product accumulation in its tissue, accompanied by SH group oxidation of crystallins due to decrease of reduced glutathione concentration in the lens. The injection of LPO products into the vitreous has been shown to induce cataract. It was concluded that peroxide damage of the lens fiber membranes may be the initiatory cause of cataract development.

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This results in the damage of the macromolecules of the lens cells, a process that compromises lens transparency and leads to cataract formation. The main targets of oxidative stress in the lens are its proteins, lipids, and nucleic acids (Babizhayev et al., 1988; Erol Tinaztepe et al., 2017; Vrensen et al., 2016). At the nucleic acid level, ROS can impair DNA repair mechanisms leading to the accumulation of genomic DNA strand breaks.
Cataract is the leading cause of blindness worldwide and surgery is the only option to treat the disease. Although the surgery is considered to be relatively safe, complications may occur in a subset of patients and access to ophthalmic care may be limited. Due to a growing and ageing population, an increase in cataract prevalence is expected and its management will become a socioeconomic challenge. Hence, there is a need for an alternative to cataract surgery. It is well known that oxidative stress is one of the main pathological processes leading to the generation of the disease. Antioxidant supplementation may, therefore, be a strategy to delay or to prevent the progression of cataract. Caffeine is a widely consumed high-potency antioxidant and may be of interest for the prevention of the disease. This review aims to give an overview of the anatomy and function of the lens, its antioxidant and reactive oxygen species (ROS) composition, and the role of oxidative stress in cataractogenesis. Also, the pharmacokinetics and -dynamics of caffeine will be described and the literature will be reviewed to give an overview of its anti-cataract potential and its possible role in the prevention of the disease.
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Several reviews have explored links between lens age and the onset of pathology (Asbell et al., 2005; Michael and Bron, 2011; Lam et al., 2015). In the lens, increasing age is accompanied by a decrease in lens concentrations of antioxidants (Chang et al., 2013; Wang et al., 2015), and increased oxidative stress-induced damage to lens proteins (Boscia et al., 2000; Wang et al., 2017), lipids (Bhuyan et al., 1986; Babizhayev et al., 1988) and DNA (Osnes-Ringen et al., 2013; Tinaztepe et al., 2017). This damage is also observed in lens epithelia of cataract patients (Katta et al., 2013; Papadopoulou et al., 2018).
Lens homeostasis and transparency are dependent on the function and intercellular communication of its epithelia. While the lens epithelium is uniquely equipped with functional repair systems to withstand reactive oxygen species (ROS)-mediated oxidative insult, ROS are not necessarily detrimental to lens cells. Lens aging, and the onset of pathogenesis leading to cataract share an underlying theme; a progressive breakdown of oxidative stress repair systems driving a pro-oxidant shift in the intracellular environment, with cumulative ROS-induced damage to lens cell biomolecules leading to cellular dysfunction and pathology. Here we provide an overview of our current understanding of the sources and essential functions of lens ROS, antioxidative defenses, and changes in the major regulatory systems that serve to maintain the finely tuned balance of oxidative signaling vs. oxidative stress in lens cells. Age-related breakdown of these redox homeostasis systems in the lens leads to the onset of cataractogenesis. We propose eight candidate hallmarks that represent common denominators of aging and cataractogenesis in the mammalian lens: oxidative stress, altered cell signaling, loss of proteostasis, mitochondrial dysfunction, dysregulated ion homeostasis, cell senescence, genomic instability and intrinsic apoptotic cell death.
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Accumulative ROS production and an impaired antioxidative defense system are also accompanied by increased lipid peroxidation [20–22], which has been found to have increased linearly in the human lens during aging [23]. A growing consensus postulates that lipid peroxidation is a pathogenic factor in cataractogenesis [24–27]. Ferroptosis is a new type of regulated cell death first proposed by Dixon et al., in 2012 [28] and defined as excessive phospholipid (PLs) peroxidation catalyzed by intracellular redox-active iron.
Age-related cataracts (ARC) are the primary cause of blindness worldwide, and oxidative stress is considered the central pathogenesis of age-related cataractogenesis. Interestingly, ample evidence suggests that there is no remarkable apoptosis present in aged and cataractous human lenses despite the profound disruption of redox homeostasis, raising an essential question regarding the existence of other cell death mechanisms. Here we sought to explore the lens epithelial cell's (LEC) susceptibility to ferroptosis after documentation has concluded that aged and cataractous human lenses manifest with increased reactive oxygen species (ROS) formation, elevated lipid peroxidation, and accumulative intracellular redox-active iron, constituting the three hallmarks of ferroptosis during aging and cataractogenesis. Here we show that very low concentrations of system X_c^- inhibitor Erastin (0.5 μM) and glutathione peroxidase 4 (GPX4) inhibitor RSL3 (0.1 μM) can drastically induce human LEC (FHL124) ferroptosis in vitro and mouse lens epithelium ferroptosis ex vivo. Depletion of intracellular glutathione (GSH) in human LECs and mouse lens epithelium significantly sensitizes ferroptosis, particularly under RSL3 challenge. Intriguingly, both human LECs and the mouse lens epithelium demonstrate an age-related sensitization of ferroptosis. Transcriptome analysis indicates that clusters of genes are up-or down-regulated in aged LECs, impacting cellular redox and iron homeostases, such as downregulation of both cystine/glutamate antiporter subunits SLC7A11 and SLC3A2 and iron exporter ferroportin (SLC40A1). Here, for the first time, we are suggesting that LECs are highly susceptible to ferroptosis. Moreover, aged and cataractous human lenses may possess more pro-ferroptotic criteria than any other organ in the human body.
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Furthermore, products of lipid oxidation impede membrane function and alter relevant cellular processes such as growth, respiration, and ATPase and phosphate transport, as well as DNA, RNA, and protein synthesis (93). The association between lipid oxidation and lens opacity is very strong and has led many to state that lipid oxidation may be the initiating pathogen of human cataract (92–100). Changes in lens lipid composition with age and cataract are due to the preferential oxidation of glycerophospholipids, as explained below (3, 13, 43, 74, 75).
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This study addresses the question: why do rats get cataracts at 2 years, dogs at 8 years, and whales do not develop cataracts for 200 years? Whale lens lipid phase transitions were compared with the phase transitions of other species that were recalculated. The major phospholipids of the whale lens were sphingolipids, mostly dihydrosphingomyelins with an average molar cholesterol/phospholipid ratio of 10. There was a linear correlation between the percentage of lens sphingolipid and lens lipid hydrocarbon chain order until about 60% sphingolipid. The percentage of lens sphingolipid correlated with the lens lipid phase transition temperature. The lifespan of the bowhead whale was the longest of the species measured and the percentage of whale lens sphingolipid fit well in the correlation between the percentage of lens sphingolipid and lifespan for many species. In conclusion, bowhead whale lens membranes have a high sphingolipid content that confers resistance to oxidation, allowing these lenses to stay clear relatively longer than many other species. The strong correlation between sphingolipid and lifespan may form a basis for future studies, which are needed because correlations do not infer cause. One could hope that if human lenses could be made to have a lipid composition similar to whales, like the bowhead, humans would not develop age-related cataracts for over 100 years.

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Lipid peroxidation as a possible cause of cataract

Abstract

Exp. Eye Res.

Biochim. Biophys. Acta

Exp. Eye Res.

Exp. Eye Res.

Exp. Eye Res.

Exp. Eye Res.

Exp. Eye Res.

J. Biol. Chem.

Anal. Biochem.

Exp. Eye Res.

Arch. Biochem. Biophys.

The search for a solution to senile cataracts

Invest. Ophthalmol. Vis Sci.

The lens proteins

Biochemistry of membranes

Damage to microsomal membrane by lipid peroxidation

Lipids

Lipid peroxidation damage to cell components

Studies on glutathione S-transferase, glutathione peroxidase and glutathione reductase in human normal and cataractous lenses

Opththalmic Res.

Photoperoxidation in lens and cataract formation: preventive role of superoxide dismutase, catalase and vitamin C

Ophthalmic Res.