Thioredoxin 2 haploinsufficiency in mice results in impaired mitochondrial function and increased oxidative stress
Viviana I Pérez1, Christie M Lew, Lisa A Cortez
1The Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, 15355 Lambda Drive, San Antonio, TX 78229, USA.
Abstract:
The mitochondrial form of thioredoxin, thioredoxin 2 (Txn2), plays an important role in redox control and protection against ROS-induced mitochondrial damage. To evaluate the effect of reduced levels of Txn2 in vivo, we measured oxidative damage and mitochondrial function using mice heterozygous for the Txn2 gene (Txn2(+/-)). The Txn2(+/-) mice showed approximately 50% decrease in Trx-2 protein expression in all tissues without upregulating the other major components of the antioxidant defense system. Reduced levels of Txn2 resulted in decreased mitochondrial function as shown by reduced ATP production by isolated mitochondria and reduced activity of electron transport chain complexes (ETCs). Mitochondria isolated from Txn2(+/-) mice also showed increased ROS production compared to wild type mice. The Txn2(+/-) mice showed increased oxidative damage to nuclear DNA, lipids, and proteins in liver. In addition, we observed an increase in apoptosis in liver from Txn2(+/-) mice compared with wild type mice after diquat treatment. Our results suggest that Txn2 plays an important role in protecting the mitochondria against oxidative stress and in sensitizing the cells to ROS-induced apoptosis.
Insights
Reduced thioredoxin 2 (Txn2) levels impair mitochondrial function and increase oxidative damage. This highlights Txn2's crucial role in protecting mitochondria against reactive oxygen species (ROS) and preventing apoptosis.
Area of Science:
- Mitochondrial biology
- Redox homeostasis
- Cellular stress response
Background:
- Thioredoxin 2 (Txn2) is vital for mitochondrial redox control and protection against reactive oxygen species (ROS).
- Understanding the in vivo consequences of diminished Txn2 levels is crucial for elucidating its protective mechanisms.
Purpose of the Study:
- To investigate the effects of reduced thioredoxin 2 (Txn2) levels on mitochondrial function and oxidative damage in vivo.
- To evaluate the role of Txn2 in cellular defense against ROS-induced damage and apoptosis.
Main Methods:
- Utilized heterozygous Txn2 gene knockout mice (Txn2(+/-)) to model reduced Txn2 protein expression.
- Assessed mitochondrial function via ATP production and electron transport chain (ETC) complex activity.
- Quantified ROS production, oxidative damage markers (DNA, lipids, proteins), and apoptosis levels in liver tissues.
Main Results:
- Txn2(+/-) mice exhibited ~50% lower Trx-2 protein levels without compensatory antioxidant upregulation.
- Mitochondria from Txn2(+/-) mice showed impaired ATP production, reduced ETC activity, and increased ROS generation.
- Significant increases in oxidative damage to DNA, lipids, and proteins were observed in the livers of Txn2(+/-) mice.
- Txn2(+/-) mice displayed heightened susceptibility to diquat-induced apoptosis in liver tissues.
Conclusions:
- Thioredoxin 2 (Txn2) is essential for maintaining mitochondrial integrity and function under oxidative stress.
- Reduced Txn2 levels compromise cellular defense mechanisms, leading to increased oxidative damage and apoptosis.
- Txn2 plays a critical role in protecting mitochondria against ROS and modulating apoptosis pathways.
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