Regulation of Mitochondrial Biogenesis in Diabetic Retinopathy

Area of Science:

• Molecular Biology
• Ophthalmology
• Metabolic Diseases

Background:

• Mitochondrial dysfunction is central to diabetic retinopathy (DR) development and its persistence despite normal glucose levels (metabolic memory).
• Long noncoding RNAs (lncRNAs) are dysregulated in diabetes and can resist normalization after hyperglycemia cessation.
• LncRNA HOTAIR, a chromatin regulator, is implicated in various cellular processes.

Purpose of the Study:

• To investigate the role of lncRNA HOTAIR in mitochondrial biogenesis within the context of diabetic retinopathy.
• To explore HOTAIR's involvement in the phenomenon of metabolic memory in retinal cells.
• To assess HOTAIR as a potential therapeutic target for DR.

Main Methods:

• Retinal endothelial and Müller cells were cultured in high glucose (20 mM) or normal glucose (5 mM).
• HOTAIR-siRNA was used to inhibit HOTAIR expression.
• Mitochondrial biogenesis was assessed by quantifying mitochondrial mass, copy number, mtDNA replication, structure, and function. Metabolic memory was studied by switching from high to normal glucose conditions post-treatment.

Main Results:

• HOTAIR was upregulated in both vascular and nonvascular retinal cells under high glucose conditions.
• HOTAIR inhibition (HOTAIR-siRNA) restored mitochondrial biogenesis and protected mitochondrial structure/function.
• High glucose-induced HOTAIR upregulation and impaired mitochondrial biogenesis persisted even after glucose normalization, indicating metabolic memory. However, HOTAIR regulation during high glucose exposure prevented mitochondrial deficits.

Conclusions:

• LncRNA HOTAIR significantly contributes to mitochondrial dysfunction and impaired biogenesis in diabetic retinopathy.
• HOTAIR plays a critical role in maintaining mitochondrial deficits associated with metabolic memory in retinal cells.
• Targeting HOTAIR presents a promising therapeutic avenue for preventing or treating diabetic retinopathy.