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MITF protects against oxidative damage-induced retinal degeneration by regulating the NRF2 pathway in the retinal
Shuxian Han1, Jianjun Chen2, Jiajia Hua3
1Laboratory of Developmental Cell Biology and Disease, School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, China; State Key Laboratory Cultivation Base and Key Laboratory of Vision Science of Ministry of Health and Zhejiang Provincial Key Laboratory of Ophthalmology, Wenzhou Medical University, Wenzhou, 325003, China.
Abstract:
Oxidative damage is one of the major contributors to retinal degenerative diseases such as age-related macular degeneration (AMD), while RPE mediated antioxidant defense plays an important role in preventing retinopathies. However, the regulatory mechanisms of antioxidant signaling in RPE cells are poorly understood. Here we show that transcription factor MITF regulates the antioxidant response in RPE cells, protecting the neural retina from oxidative damage. In the oxidative stress-induced retinal degeneration mouse model, retinal degeneration in Mitf+/- mice is significantly aggravated compared to WT mice. In contrast, overexpression of Mitf in Dct-Mitf transgenic mice and AAV mediated overexpression in RPE cells protect the neural retina against oxidative damage. Mechanistically, MITF both directly regulates the transcription of NRF2, a master regulator of antioxidant signaling, and promotes its nuclear translocation. Furthermore, specific overexpression of NRF2 in Mitf+/- RPE cells activates antioxidant signaling and partially protects the retina from oxidative damage. Taken together, our findings demonstrate the regulation of NRF2 by MITF in RPE cells and provide new insights into potential therapeutic approaches for prevention of oxidative damage diseases.
Insights
Microphthalmia-associated transcription factor (MITF) regulates antioxidant responses in retinal pigment epithelium (RPE) cells. MITF protects the neural retina from oxidative damage by controlling NRF2, offering therapeutic insights for retinal diseases.
Area of Science:
- Ophthalmology
- Molecular Biology
- Cell Biology
Background:
- Oxidative damage contributes to retinal degenerative diseases like age-related macular degeneration (AMD).
- Retinal pigment epithelium (RPE) cells provide antioxidant defense, but regulatory mechanisms are unclear.
- Understanding these mechanisms is crucial for preventing retinopathies.
Purpose of the Study:
- To investigate the role of transcription factor MITF in regulating antioxidant signaling in RPE cells.
- To elucidate the molecular mechanisms by which MITF influences antioxidant defense.
- To explore therapeutic strategies for oxidative damage-related retinal diseases.
Main Methods:
- Utilized an oxidative stress-induced retinal degeneration mouse model.
- Compared retinal degeneration in wild-type (WT), Mitf+/- mice, and transgenic mice overexpressing Mitf.
- Employed adeno-associated virus (AAV) mediated gene delivery for RPE-specific Mitf and NRF2 overexpression.
- Assessed MITF's direct regulation of NRF2 transcription and nuclear translocation.
Main Results:
- Mitf+/- mice exhibited aggravated retinal degeneration under oxidative stress compared to WT mice.
- Overexpression of Mitf in RPE cells protected the neural retina from oxidative damage.
- MITF directly regulates NRF2 transcription and promotes its nuclear translocation.
- NRF2 overexpression in Mitf+/- RPE cells partially restored antioxidant signaling and retinal protection.
Conclusions:
- MITF plays a critical role in regulating the antioxidant response in RPE cells via NRF2.
- MITF-mediated regulation of NRF2 is a key protective mechanism against oxidative damage in the retina.
- These findings offer novel therapeutic targets for preventing and treating oxidative damage-related retinal diseases.
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