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M. Marchetti, T.L. Cowell, T.M. Wells, M. Kantorow; Methionine Sulfoxide Reductase A Is Required for Mitochondrial Function in Human Lens Cells . Invest. Ophthalmol. Vis. Sci. 2006;47(13):4121.
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© ARVO (1962-2015); The Authors (2016-present)
Methionine sulfoxide accumulation is a major feature of age–related cataract that can be repaired by a unique class of enzymes called Methionine sulfoxide reductases (Msrs) that act on R–and S–forms of protein methionine sulfoxide (PMSO). MsrA is specific for S–PMSO while three distinct MsrBs called B1, B2 and B3 are specific for R–PMSO. Deletion of MsrA results in loss of lifespan and the protein is localized to the mitochondria suggesting an important function for MsrA in mitochondrial maintenance. In the present study, we sought to establish a potential role for MsrA in the maintenance of human lens cell mitochondria.
Lens epithelial cells expressing different levels of MsrA mRNA were generated by targeted gene silencing with different MsrA–specific siRNA sequences. The resulting cells were monitored for viability; loss of mitochondrial membrane potential, increased reactive oxygen species (ROS) and increased apoptosis and/or necrosis in the presence and absence of t–butyl hydrogenperoxide (TBHP).
Lens cell viability was lost in direct proportion to the level of MsrA gene expression under standard culture conditions in the absence of exogenously added oxidative stress (OS). Loss of viability occurred with concomitant loss of mitochondrial membrane potential and increased ROS levels. Interestingly, only apoptosis occurred upon MsrA gene silencing in the absence of oxidative stress but both apoptosis and necrosis were observed in the presence of oxidative stress.
The present data confirm that MsrA plays an important role in the normal maintenance of lens cells and provides evidence that MsrA is required for lens cell mitochondrial function. The data also suggest that ROS levels are tied to mitochondrial function and that loss of mitochondrial function is likely to play a key role in the development of age–related cataract and other age–related degenerative diseases.
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