Activated mTOR Signaling in the RPE Drives EMT, Autophagy, and Metabolic Disruption, Resulting in AMD-Like Pathology in Mice

Aging Cell. 2025 Jun;24(6):e70018. doi: 10.1111/acel.70018. Epub 2025 Feb 17.

Abstract

The mechanistic target of rapamycin (mTOR) complexes 1 and 2 (mTORC1/2) are crucial for various physiological functions. Although the role of mTORC1 in retinal pigmented epithelium (RPE) homeostasis and age-related macular degeneration (AMD) pathogenesis is established, the function of mTORC2 remains unclear. We investigated both complexes in RPE health and disease. Therefore, in this study, we have attempted to demonstrate that the specific overexpression of mammalian lethal with Sec13 protein 8 (mLST8) in the mouse RPE activates both mTORC1 and mTORC2, inducing epithelial-mesenchymal transition (EMT)-like changes and subretinal/RPE deposits resembling early AMD-like pathogenesis. Aging in these mice leads to RPE degeneration, causing retinal damage, impaired debris clearance, and metabolic and mitochondrial dysfunction. Inhibition of mTOR with TORIN1 in vitro or βA3/A1-crystallin in vivo normalized mTORC1/2 activity and restored function, revealing a novel role for the mTOR complexes in regulating RPE function, impacting retinal health and disease.

Keywords: RPE; epithelial–mesenchymal transition; mLST8; mTOR complex 1; mTOR complex 2; metabolic/mitochondrial changes.

MeSH terms

  • Animals
  • Autophagy*
  • Epithelial-Mesenchymal Transition*
  • Humans
  • Macular Degeneration* / genetics
  • Macular Degeneration* / metabolism
  • Macular Degeneration* / pathology
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Mechanistic Target of Rapamycin Complex 2 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Retinal Pigment Epithelium* / metabolism
  • Retinal Pigment Epithelium* / pathology
  • Signal Transduction*
  • TOR Serine-Threonine Kinases* / metabolism

Substances

  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 2
  • Mechanistic Target of Rapamycin Complex 1
  • mTOR protein, mouse