Abstract
A key feature of many age-related diseases is the oxidative stress-induced accumulation of protein methionine sulfoxide (PMSO) which causes lost protein function and cell death. Proteins whose functions are lost upon PMSO formation can be repaired by the enzyme methionine sulfoxide reductase A (MsrA) which is a key regulator of longevity. One disease intimately associated with PMSO formation and loss of MsrA activity is age-related human cataract. PMSO levels increase in the eye lens upon aging and in age-related human cataract as much as 70% of total lens protein is converted to PMSO. MsrA is required for lens cell maintenance, defense against oxidative stress damage, mitochondrial function and prevention of lens cataract formation. Essential for MsrA action in the lens and other tissues is the availability of a reducing system sufficient to catalytically regenerate active MsrA. To date, the lens reducing system(s) required for MsrA activity has not been defined. Here, we provide evidence that a novel thioredoxin-like protein called thioredoxin-like 6 (TXNL6) can serve as a reducing system for MsrA repair of the essential lens chaperone α-crystallin/sHSP and mitochondrial cytochrome c. We also show that TXNL6 is induced at high levels in human lens epithelial cells exposed to H2O2-induced oxidative stress. Collectively, these data suggest a critical role for TXNL6 in MsrA repair of essential lens proteins under oxidative stress conditions and that TXNL6 is important for MsrA defense protection against cataract. They also suggest that MsrA uses multiple reducing systems for its repair activity that may augment its function under different cellular conditions.
Highlights
Significant evidence points to a major role for protein oxidations in the etiology of many age-related human degenerative disorders including Alzheimer’s disease [1,2], Parkinson’s disease [3,4,5], and age-related cataract of the eye lens [6]
Our results indicate that in addition to the retina [38], thioredoxin-like 6 (TXNL6) is expressed in the human eye lens and multiple other human tissues, that TXNL6 co-localizes with methionine sulfoxide reductase A (MsrA) in the cytosol and the mitochondria of lens cells, that TXNL6 expression is inducible in lens cells upon oxidative stress exposure, and most importantly, that TXNL6 acts as a novel reducing system for MsrA repair of cyt c and a-crystallin/sHSP
The lens epithelial cells contain intact organelles and the majority of transporters and metabolic enzymes in the lens [47,48], while the fiber cells are for the most part devoid of organelles and contain the majority of structural crystallin proteins required for light refraction and lens transparency [49]
Summary
Significant evidence points to a major role for protein oxidations in the etiology of many age-related human degenerative disorders including Alzheimer’s disease [1,2], Parkinson’s disease [3,4,5], and age-related cataract of the eye lens [6]. Protein oxidation can result in altered conformation, activity, sub-cellular localization patterns, and aggregation states which are associated with loss of cellular functions, apoptosis, and cell death [7]. Proteins become oxidized upon exposure to reactive oxygen species (ROS). ROS levels increase upon aging as a consequence of multiple events including age-related accumulation of mitochondrial mutations, resulting from exposure to endogenous ROS [11]. The two most common protein oxidations upon aging and disease are oxidation of cysteines and methionines [7][12][13]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
