LAPTM5 correlates with RPE senescence and subretinal fibrosis through the LAPTM5-WWP2-OPTN mitophagy cascade and...

Retinal pigment epithelium (RPE) senescence acts as a core driver of subretinal fibrosis, a major irreversible pathological feature that exacerbates age-related macular degeneration (AMD). Mitophagy is essential for maintaining RPE homeostasis during aging. However, the upstream molecular mechanisms underlying mitophagy impairment in senescent RPE remain poorly defined. Here, we show that lysosomal-associated transmembrane protein 5 (LAPTM5) is significantly upregulated in human AMD specimens and D-galactose (D-gal)-induced aging mouse model, with its overexpression correlating with transcriptomic signatures of RPE senescence and fibrogenesis. Gain- and loss-of-function assays validate that LAPTM5 acts as an important regulator of RPE senescence and senescence-associated secretory phenotype (SASP) production. Mechanistically, LAPTM5 physically interacts with and promotes the lysosome-dependent degradation of WW domain-containing E3 ubiquitin protein ligase 2 (WWP2), which in turn diminishes optineurin (OPTN) polyubiquitination and ablates OPTN-mediated mitophagy. The resulting mitophagy deficiency is associated with cytoplasmic mitochondrial DNA leakage and sustained cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) innate immune activation, stimulating robust senescence-associated secretory phenotype (SASP) release that promotes RPE epithelial-mesenchymal transition (EMT) and exacerbates subretinal fibrotic scarring. Notably, AAV-mediated RPE-specific Laptm5 knockdown efficiently alleviates subretinal fibrotic lesions in the aged mouse model, while pharmacological STING inhibition with H-151 markedly attenuates EMT progression. Collectively, our findings identify a previously uncharacterized LAPTM5-WWP2-OPTN mitophagy cascade and reveal a new pathogenic circuit linking impaired mitophagy to RPE senescence and age-related retinal fibrosis, offering translational prospects for treating senescence-associated fibrotic diseases.