ReviewMitochondrial function and redox control in the aging eye: Role of MsrA and other repair systems in cataract and macular degenerations
Introduction
Maintaining the redox balance within the mitochondria is critical for cellular homeostasis since the mitochondria house the energy producing systems of the cell and it is widely recognized that damage to the mitochondria plays a key role in aging and age-related disorders. Production of reactive oxygen species (ROS) such as the hydroxyl radical (OH), singlet oxygen (1O2), hydrogen peroxide (H2O2) and peroxynitrite (OONO−) is finely balanced with sophisticated antioxidant and repair systems located in this complex organelle. Loss of these systems leads to protein oxidations that are hallmarks of many ocular diseases including cataract and retinal degeneration. The two most oxidizable protein amino acids are methionine and cysteine making mitochondrial systems that protect or repair these of particular interest. This review is an attempt to integrate how mitochondrial ROS are altered in the aging eye, along with those protective and repair systems believed to regulate ROS levels in this tissue and how damage to these systems contributes to age-onset eye disease. Given the enormity, complexity and wide ranging importance of these systems we undoubtedly have overlooked many critically important aspects of this area. In particular, redox regulation of signaling systems has not been included. Possible omissions in this regard in no way diminish the importance of these areas and we apologize in advance for any omissions.
Section snippets
ROS and aging
ROS are believed to arise in cells from exogenous (environmental) and endogenous sources. Exogenous sources of ROS include UV light, visible light, ionizing radiation, chemotherapeutics, and environmental toxins. Endogenous sources include activity of peroxisomes, lipoxygenases NADH oxidase, cytochrome P450 and of course mitochondrial respiration. In humans, ROS have been implicated in a variety of human diseases including cancer, type II diabetes, arteriosclerosis, chronic inflammatory
Mitochondria and ROS
Mitochondria are sometimes referred to as the powerhouses of the cell since they generate most of the cells' chemical energy requirement in the form of adenosine triphosphate (ATP). They also have a significant role in regulating apoptosis and necrosis, ROS levels, cellular signaling, control of the cell cycle, and growth and differentiation (Pedersen, 1999). Mitochondria are also involved in calcium uptake and release, production of NADH, synthesis of DNA, RNA and proteins, DNA repair and
Mitochondria and eye tissues
Tissues with high energy demands such as muscles, heart, liver, endocrine glands, brain and retina, have higher numbers of mitochondria per cell. Distribution of mitochondria in the lens is associated with its development. The lens is composed of cells that differentiate from an anterior layer of cuboidal epithelia and migrate posteriorly to form elongated lens fiber cells that make up the lens nucleus. During this process fiber cells synthesize high levels of lens crystallins before losing
Mitochondrial diseases
Over 100 mutations in mtDNA have been identified in various tissues in aged individuals leading to defects in respiratory function. Mutations can affect specific proteins of the respiratory chain or the synthesis of mitochondrial proteins by mutations in any of the genes coding for necessary RNAs. Mitochondrial diseases result from defects in respiration and oxidative phosphorylation, which lead to decreased ATP synthesis and increased production of ROS. Point mutations in particular can result
Mitochondrial reducing systems
Reducing systems in the mitochondria employ electron donors such as glutathione (GSH), thioredoxin (Trx), NADPH, NADH, FADH2 and certain amino acids. Reducing equivalents act as important electron donors in order to maintain the redox status of a number of essential proteins and aid antioxidant enzyme systems. In the eye, GSH is a primary protectant of lens, cornea, and retina against ROS-induced damage (Ganea and Harding, 2006). The eye lens in particular contains high levels of reduced GSH,
Mitochondrial protective and repair systems
Mitochondrial protection and repair is mediated by the reducing agents detailed above, primary antioxidants and chaperones, antioxidant enzymes and specific protein repair systems. In the mitochondria all of the systems work in concert to protect against ROS-induced damage.
In the eye, primary antioxidants that directly scavenge ROS, such as vitamin C and E and the carotenoids are well studied. Although in vivo and in vitro animal studies have linked antioxidants and cataract, data showing a
The methionine sulfoxide reductase repair system
Msrs are a family of thioredoxin dependent oxidoreductases that reduce methionine sulfoxide back to its reduced form methionine. Two classes of Msrs are known; MsrA and MsrB which act on S- and R-epimers of methionine sulfoxide (MSO), respectively. Repair of oxidized methionine has been shown to protect against oxidative stress in a number of cells, oxidation of methionine may lead to significant changes in protein structure and functions. Eight targets for MsrA have been reported including
The proteasome
The proteasome is responsible for protein turnover and removal of irretrievably damaged proteins; it deals with proteolysis of oxidized proteins in the cytosol and nucleus while the lon protease, an ATP-stimulated mitochondrial matrix protein, is responsible for degradation of such proteins in the mitochondrial matrix. There are three enzymatic activities associated with the proteasome: postglutamyl peptide hydrolysing (PGPH), trypsin-like and chymotrypsin-like cleavage. Proteasome activities
Mitochondrial ROS systems and cataract
Cataract, the opacification of the crystalline lens, is one of the leading causes of blindness in the world. Already over 50% of Americans over the age of 65 are affected and this is expected to increase over the next 10 years as the population ages, in fact it is estimated that 30.1 million Americans will have cataracts by 2020 (Center for Disease Control and Prevention, 2006). Cataracts therefore present a significant health problem in the US and place a major burden on the economy.
Aging is
Mitochondrial ROS systems and maculopathy
Maculopathies are a diverse group of blinding disorders characterized by loss of central vision associated with retinal pigmented epithelium (RPE) atrophy with or without choroidal neovascularization. Age-related macular degeneration (ARMD) accounts for 50% of all cases of blindness in the United States of America and Western Europe (Resnikoff et al., 2004). This degenerative disease progresses from waxy retinal deposits called drusen to neovascularization and retinal hemorrhage, eventually
Summary
In summary oxidation and reduction reactions clearly play a significant role in pathogenesis of eye disease. Multiple mitochondrial antioxidant and repair systems work in concert to maintain transparency in the lens and retinal function. It is clear that oxidation and cross-linking of proteins has a significant role to play in the pathogenesis of cataracts, ARMD (Hollyfield et al., 2008) and some of the monogenic maculopathies. Aging of the eye is characterized by increased ROS, decreased
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