The transcription factor Nrf2 promotes survival by enhancing the expression of uncoupling protein 3 under conditions of oxidative stress.
2013
Abstract Uncoupling protein 3 (UCP3) is a member of the mitochondrial inner membrane carrier superfamily that modulates energy efficiency by catalyzing proton conductance and thus decreasing the production of superoxide anion. However, its role during oxidative stress and the underlying regulatory and molecular mechanisms remain poorly understood. We sought to investigate how UCP3 expression is regulated by oxidative stress and to evaluate the putative antioxidant role of this protein. H 2 O 2 treatment increased UCP3 expression and the nuclear accumulation of the transcription factor Nrf2 in C2C12 and HL-1 cells. Nrf2 siRNA prevented H 2 O 2 -induced UCP3 expression, increasing oxidative stress and cell death. ChIP assays identified an antioxidant-response element (ARE) within the UCP3 promoter that bound Nrf2 after exposure to H 2 O 2 . Luciferase reporter experiments confirmed increased ARE activity in H 2 O 2 -treated HL-1 cells. Importantly, H 2 O 2 increased the UCP3-mediated proton leak, suggesting a role for this protein in attenuating ROS-induced damage. Nrf2 nuclear accumulation and increased UCP3 protein were also detected in intact mouse heart subjected to a condition known to increase ROS generation. This is the first study to demonstrate that H 2 O 2 augments UCP3 expression and it provides the first evidence of Nrf2 binding to the UCP3 promoter in response to oxidative challenge. These findings suggest that UCP3 functions as a member of the cellular antioxidant defense system that protects against oxidative stress in vivo . In conclusion, we have identified a novel regulatory process induced by an oxidative insult whereby the expression of the mitochondrial protein UCP3 is driven by the Nrf2 transcription factor, which decreases ROS production and prevents cell death.
Keywords:
- Correction
- Source
- Cite
- Save
- Machine Reading By IdeaReader
56
References
65
Citations
NaN
KQI