Modulation of mTOR Within Retinal Pigment Epithelium Affects Cell Viability and Mitochondrial Pathology

TL;DR

This study shows that modulating mTOR in retinal pigment epithelium affects cell survival and mitochondrial health, with implications for age-related macular degeneration.

Contribution

The study demonstrates that mTOR modulation directly impacts mitochondrial integrity and RPE cell viability, offering new therapeutic insights for AMD.

Findings

3-MA activates mTOR, leading to cell death and mitochondrial damage in RPE cells.

Curcumin and rapamycin counteract mTOR activation, preserving mitochondrial health and preventing RPE cell loss.

mTOR inhibition may protect mitochondria and reduce pathology in retinal degeneration.

Abstract

The relevance of well-structured mitochondria in sustaining the integrity of the retinal pigment epithelium (RPE) is increasingly evident. Conversely, altered mitochondria are a culprit of age-related macular degeneration (AMD), which is influenced by the activity of mechanistic target of rapamycin (mTOR). In the present manuscript, the mitochondrial status of RPE cells was investigated by light and electron microscopy following the administration of various doses of compounds, which modulate mTOR. The study combines MitoTracker dyes and mitochondrial immunohistochemistry with in situ mitochondrial morphometry. Various doses of 3-methyladenine (3-MA), curcumin, and rapamycin were administered alone or in combination. The activity of autophagy and mTOR was quantified following each treatment. Administration of 3-MA led to activation of mTOR, which was associated with severe cell death, altered membrane permeability, and altered ZO-1 expression. In this condition, mitochondrial mass was reduced, despite a dramatic increase in damaged mitochondria being reported. The decrease in healthy mitochondria was concomitant with alterations in key mitochondria-related antigens such as Tomm20, Pink1, and Parkin. Specific mitochondrial alterations were quantified through in situ ultrastructural morphometry. Both curcumin and rapamycin counteract mTOR activation and rescue mitochondrial status, while preventing RPE cell loss and misplacement of decreased ZO-1 expression. Mitigation of mTOR may protect mitochondria in retinal degeneration.

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