<scp>METTL14</scp> Ameliorates Mitochondrial Dysfunction and Autophagy in Lens Epithelial Cells of Diabetic Cataracts via <scp>m6A</scp> Modification of <scp>RPL3</scp>

Diabetic cataracts are a leading cause of blindness, with lens epithelial cells (LECs) exhibiting mitochondrial dysfunction and autophagy inhibition under high glucose (HG) conditions. Methyltransferase-like 14 (METTL14), an RNA methyltransferase, regulates N6-methyladenosine (m6A) RNA modification; however, its role in modulating mitochondrial function and autophagy in LECs under diabetic conditions remains poorly understood. This study aims to explore the effects of METTL14 on mitochondrial dysfunction and autophagy in LECs under HG conditions and to investigate the underlying mechanism involving m6A modification of ribosomal protein L3 (RPL3). Primary LECs exposed to HG showed reduced viability, increased reactive oxygen species (ROS), decreased adenosine triphosphate (ATP) levels, and loss of mitochondrial membrane potential (MMP), alongside suppressed autophagy. Knockdown of METTL14 worsened these deficits, while METTL14 overexpression alleviated them. Mechanistically, METTL14 increased m6A modification on RPL3 mRNA, enhancing RPL3 expression. Overexpressing RPL3 improved mitochondrial function, whereas knocking down RPL3 abolished the protective effects of METTL14 overexpression. In diabetic mouse models, adeno-associated virus (AAV)-mediated METTL14 overexpression improved lens transparency and reduced oxidative stress, benefits that were reversed by concurrent RPL3 knockdown. In conclusion, METTL14 mitigates HG-induced mitochondrial dysfunction and autophagy inhibition in LECs by promoting m6A-dependent upregulation of RPL3, identifying the METTL14/RPL3 axis as a promising target for diabetic cataract therapy.