Description
Age-related macular degeneration (AMD) is the primary cause of legal blindness in the developed world. However, AMD remains incompletely understood due to a complex interplay of genetic and environmental factors and currently lacks an effective cure. Central to disease progression is degeneration of the retinal pigment epithelium (RPE), which is essential for photoreceptor homeostasis. Although RPE mitochondrial dysfunction and extracellular matrix (ECM) alterations have been strongly implicated, the pathogenic sequence linking these processes remains unclear. Here, we sought to elucidate AMD pathogenesis by interrogating a hiPSC-derived RPE model of the monogenic mitochondrial disorder caused by the mt.3243A>G mutation, which can manifest with macular degeneration in young patients. We compared isogenic hiPSC-derived RPE clones harbouring low, intermediate, or high levels of mt.3243A>G heteroplasmy, assessing bioenergetics, cell identity, and transcriptomic changes by RNA-seq. Our results demonstrate that RPE bioenergetic and oxygen consumption were inversely correlated with heteroplasmy levels, without affecting typical RPE morphology or marker expression. Notably, transcriptomic analysis revealed significant enrichment of ECM remodelling pathways in mutant RPE in a heteroplasmy-dependent manner, predominantly orchestrated by TGF-β signalling. Integration with human AMD datasets identified shared ECM- and TGF-β–associated pathways. Mechanistically, ROS scavenging or TGF-β inhibition reduced expression of downstream ECM effectors in high-heteroplasmy RPE cells. Collectively, our mt.3243A>G disease model establishes a direct causal link between mitochondrial dysfunction and TGF-β–dependent ECM remodelling in RPE. Given the central role of these processes in AMD and mt.3243A>G-associated macular atrophy, our findings position mitochondrial dysfunction as a potential upstream driver of AMD pathogenesis and a promising therapeutic target.
Lay Abstract
Age-related macular degeneration (AMD) is one of the leading causes of vision loss, yet we still do not fully understand why it develops or how to stop it. In AMD, a layer of cells in the eye, called retinal pigment epithelium (RPE) cells, becomes damaged. These cells keep our vision working by supporting the light sensing cells in the retina.
In this study, we investigated whether problems with energy production in RPE cells might play a role. Cells rely on structures called mitochondria to generate energy. Using stem cell–derived RPE cells with different levels of a mitochondrial mutation, we examined how reduced energy affects cell behaviour.
We found that cells with higher levels of the mutation produced less energy, even though they still looked normal. However, these low energy cells showed clear changes in the extracellular matrix, the network of proteins that surrounds and supports cells. This structure is critical for maintaining healthy tissue in the eye, and its disruption is a key feature of AMD. Similar changes were also seen in patient data.
Our findings suggest that energy loss in RPE cells may drive harmful changes in their environment, contributing to AMD and pointing towards new treatment strategies.
| Lay Title | When Eye Cells Run Low on Energy: A New Clue to Macular Degeneration |
|---|---|
| Role | Postdoctoral Researcher |