Glutaredoxin 2 (Grx2) Gene Deletion Induces Early Onset of Age-dependent Cataracts in Mice

Authors

Hongli Wu, University of North Texas Health Science CenterFollow
Yibo Yu, Medical College of Zhejiang University, Hangzhou, China
Larry David, Oregon Health and Science UniversityFollow
Ye-Shih Ho, Wayne State University, DetroitFollow
Marjorie . F. Lou, University of Nebraska-LincolnFollow

Document Type

Article

Date of this Version

12-2014

Citation

Published in The Journal of Biological Chemistry 289, (December 26, 2014), pp. 36125-36139; doi: 10.1074/jbc.M114.620047

Comments

Copyright © 2014 The American Society for Biochemistry and Molecular Biology, Inc. Used by permission.

Abstract

Glutaredoxin 2 (Grx2) is an isozyme of glutaredoxin1 (thioltransferase) present in the mitochondria and nucleus with disulfide reductase and peroxidase activities, and it controls thiol/ disulfide balance in cells. In this study, we investigated whether Grx2 gene deletion could induce faster age-related cataract formation and elucidated the biochemical changes effected by Grx2 gene deletion that may contribute to lens opacity. Slit lamp was used to examine the lenses in Grx2 knock-out (KO) mice and age-matched wild-type (WT) mice ages 1 to 16 months. In the Grx2 null mice, the lens nuclear opacity began at 5 months, 3 months sooner than that of the control mice, and the progression of cataracts was also much faster than the age-matched controls. Lenses of KO mice contained lower levels of protein thiols and GSH with a significant accumulation of S-glutathionylated proteins. Actin, αA-crystallin, and βB2-crystallin were identified by Western blot and mass spectroscopy as the major S-glutathionylated proteins in the lenses of 16-month-old Grx2 KO mice. Compared with the WT control, the lens of Grx2 KO mice had only 50% of the activity in complex I and complex IV and less than 10% of the ATP pool. It was concluded that Grx2 gene deletion altered the function of lens structural proteins through S-glutathionylation and also caused severe disturbance in mitochondrial function. These combined alterations affected lens transparency.