Targeting the Mitochondrial Chaperone TRAP1 Alleviates Vascular Pathologies in Ischemic Retinopathy

Area of Science:

• Ophthalmology
• Mitochondrial Biology
• Molecular Medicine

Background:

• Hypoxia-inducible factor 1α (HIF1α) activation contributes to blood-retinal barrier (BRB) breakdown and neovascularization in ischemic retinopathies.
• Mitochondrial adaptations to ischemia are crucial in disease pathogenesis but incompletely understood.

Purpose of the Study:

• To investigate the role of mitochondrial chaperone tumor necrosis factor receptor-associated protein 1 (TRAP1) in ischemic retinopathy.
• To explore TRAP1 as a potential therapeutic target for vision-threatening retinal diseases.

Main Methods:

• Utilized mouse models of ischemic retinopathies.
• Examined the effects of genetic TRAP1 ablation and small molecule TRAP1 inhibitors (MitoQ, SB-U015).
• Assessed BRB integrity, retinal neovascularization, and HIF1α levels.

Main Results:

• TRAP1 expression is essential for BRB breakdown and pathological retinal neovascularization.
• Genetic TRAP1 ablation or inhibition reduced retinal pathologies.
• TRAP1 inhibition led to HIF1α degradation via mitochondrial permeability transition pore opening and calpain-1 activation.

Conclusions:

• TRAP1 plays a critical role in the pathogenesis of ischemic retinopathy.
• Targeting TRAP1 offers a promising therapeutic strategy for conditions like retinopathy of prematurity and proliferative diabetic retinopathy.