FTO mediated m6A demethylation of lncRNA RMRP drives mitochondrial dysfunction in diabetic cataract

Diabetic cataract is characterized by early lens opacification. This study identifies a pathogenic axis that involves the N6-methyladenosine (m6A) demethylase fat mass and obesity-associated protein (FTO) and the mitochondria-enriched long non-coding RNA (lncRNA) RMRP. Transcriptomic analysis of lens epithelial cells (LECs) under high-glucose stress revealed that lncRNA RMRP was the most significantly downregulated lncRNA, while FTO was specifically upregulated. High glucose stimulated FTO to bind to RMRP, removed its m6A methylation, and expedited its degradation. Knockdown of RMRP led to mitochondrial DNA depletion, loss of respiratory chain subunits I, III, and V, bioenergetic failure, and structural damage. Notably, inhibition of FTO restored RMRP levels and rescued mitochondrial function under high-glucose conditions. In mice, overexpression of FTO in the anterior chamber induced lens opacification and mitochondrial defects, both of which were alleviated by co-expressing RMRP. In a mouse model of streptozotocin-induced diabetes, intracameral AAV-RMRP delivery restored RMRP expression specifically in LECs, suppressed cataract formation, alleviated cellular energy deficits, and restored mitochondrial DNA copy numbers and key mitochondrial biogenesis regulators. This work uncovers a new mechanism in diabetic cataracts: chronic hyperglycemia upregulates FTO, which degrades RMRP-causing mitochondrial dysfunction and lens opacity. Critically, rescuing RMRP function in a physiologically relevant diabetic model validates it as a promising therapeutic target for diabetic cataracts.