Helping keep mitochondria healthy to keep macula cells alive

Prof Andrew Dick, University of Bristol - £243,732

This project investigated two molecules involved in energy production and immunity in the cells of the macula. A previous Macular Society funded project at Bristol University found that the loss of these molecules disrupts cell metabolism, and causes cell ageing and harmful inflammation - all of which are central to the progression of AMD. This research looked at how these molecules work in the cells and investigated whether, by introducing more of them, they could restore cell health.

What is the problem?

A layer of cells in the back of the eye called the retinal pigment epithelium (RPE) is key to maintaining the health of photoreceptors, the cells that sense light and send information to the brain. These RPE cells require a lot of energy and contain many mitochondria, which are the parts of the cells that produce energy. The high requirement for energy in the RPE can lead to mitochondria becoming damaged and result in the build-up of toxic waste which leads to inflammation, both of which are involved in the development of AMD.

What are they doing?

Professor Dick and his team investigated two molecules called IRAK-M and IL-33. The project assessed the changes that take place in cells which are missing the genes that code for IRAK-M and IL-33 and compared these to normal, healthy cells. They then re-introduced the IRAK-M and IL-33 genes to better understand how these molecules interact in the cells.

The second stage of research involved introducing the IL-33 and IRAK-M genes into the eyes of mice to see whether this could stop or slow the damage that can lead to AMD.

What did the researchers find?

They found IRAK-M levels are significantly reduced in RPE cells of older individuals and those with AMD. Additionally, they showed that loss of IRAK-M or IL-33 can harm RPE cells. When these molecules are lacking, the RPE is vulnerable to stress, less efficient in producing energy, inflamed and ultimately damaged.

By boosting IRAK-M levels, they were able to help protect the retina. Gene therapy increased IRAK-M levels and as a result ensured RPE cells survived under stress, maintained healthy energy production, reduced inflammation, and prevented the overall degeneration of the retina. 

How can this help and what’s next?

This research points to IRAK-M as a key “gatekeeper” protein that helps RPE cells resist damage from aging and stress. By restoring or boosting IRAK-M, there is an opportunity to delay or even prevent the progression of AMD before it causes serious vision problems. This could lead to a new treatment that prevents damage from happening in the first place, rather than just managing progression after advanced degeneration and severe sight loss has already occurred.