Mitochondrial function and redox control in the aging eye: role of MsrA and other repair systems in cataract and macular degenerations

Abstract

Oxidative stress occurs when the level of prooxidants exceeds the level of antioxidants in cells resulting in oxidation of cellular components and consequent loss of cellular function. Oxidative stress is implicated in wide range of age-related disorders including Alzheimer's disease, Parkinson's disease amyotrophic lateral sclerosis (ALS), Huntington's disease and the aging process itself. In the anterior segment of the eye, oxidative stress has been linked to lens cataract and glaucoma while in the posterior segment of the eye oxidative stress has been associated with macular degeneration. Key to many oxidative stress conditions are alterations in the efficiency of mitochondrial respiration resulting in superoxide (O(2)(-)) production. Superoxide production precedes subsequent reactions that form potentially more dangerous reactive oxygen species (ROS) species such as the hydroxyl radical (OH), hydrogen peroxide (H(2)O(2)) and peroxynitrite (OONO(-)). The major source of ROS in the mitochondria, and in the cell overall, is leakage of electrons from complexes I and III of the electron transport chain. It is estimated that 0.2-2% of oxygen taken up by cells is converted to ROS, through mitochondrial superoxide generation, by the mitochondria. Generation of superoxide at complexes I and III has been shown to occur at both the matrix side of the inner mitochondrial membrane and the cytosolic side of the membrane. While exogenous sources of ROS such as UV light, visible light, ionizing radiation, chemotherapeutics, and environmental toxins may contribute to the oxidative milieu, mitochondria are perhaps the most significant contribution to ROS production affecting the aging process. In addition to producing ROS, mitochondria are also a target for ROS which in turn reduces mitochondrial efficiency and leads to the generation of more ROS in a vicious self-destructive cycle. Consequently, the mitochondria have evolved a number of antioxidant and key repair systems to limit the damaging potential of free oxygen radicals and to repair damaged proteins (Fig. 1). The aging eye appears to be at considerable risk from oxidative stress. This review will outline the potential role of mitochondrial function and redox balance in age-related eye diseases, and detail how the methionine sulfoxide reductase (Msr) protein repair system and other redox systems play key roles in the function and maintenance of the aging eye.

Figure 1

Overview of the systems involved in mitochondrial ROS production and protection. The process begins with leakage of superoxide (O₂-) from complexes I and III of the electron transport chain. All other process depicted function to reduce or repair the damaging potential of this and other subsequently formed oxygen radicals. UQ – Ubiquinone, NO - nitric oxide, OONO^- - Peroxynitrite, TCA cycle – Tricarboxylic acid cycle, Prx – Peroxiredoxin, TRX(2) – Thioredoxin, TRXR2 – Thioredoxin 2 reductase, mtDNA – mitochondrial DNA, H₂O₂ – hydrogen peroxide, GRX2 – glutaredoxin, MetSO – methionine sulfoxide, Met – methionine, GPx – glutathione peroxidase, MnSOD – Manganese superoxide dismutase, CuZnSOD – Copper Zinc superoxide dismutase, GSH – Glutathione, GSSG – oxidized glutathione, OH – Hydroxyl radical, Fe²⁺ - Iron, Protein S-S – protein disulphide bonds, Protein S-H – repaired thiol groups, Cyt C – cytochrome c, VDAC – voltage dependent anion channel, APAF1 – apoptotic peptidase activating factor 1, Bax and Bak – pro apoptotic factors.