A recently published article from the lab of Emory Eye Center's Sayantan Datta presents findings that could dramatically impact the treatment of age-related macular degeneration (AMD) and other cell pathologies like cancer and fibrosis.
Appearing in the August 13 edition of the journal Autophagy, the article, Mitophagy Initiates Retrograde Mitochondrial-nuclear Signaling to Guide Retinal Pigment Cell Heterogeneity
explores the findings of Datta's five-year, National Institutes of Health (NIH) K-99/R00-funded study of mitophagy - a process by which cells regulate and maintain healthy function by processing and removing dysfunctional mitochondria.
Datta's team focused on the molecular mechanisms that connect mitophagy with AMD, a vision-robbing eye disease common among the elderly.
Currently, people with AMD may take supplements or vitamins, but there is nothing that effectively stops or reverses the process,
he said. One of our goals was to establish the scientific foundation from which a novel therapeutic treatment could be developed. We are encouraged by our findings.
Identifying epithelial to mesenchymal transition
Datta's team discovered that a disfiguration of the eye's retinal pigment epithelial (RPE) cells proceeds the deterioration of a patient's sight. These normally honeycomb-shaped cells become elongated due to a dysfunctional or dying mitochondria within them. In AMD, Datta's team found that the mitochondria was undergoing not mitophagy, but epithelial to mesenchymal transition (EMT). The EMT process destroys the stability of RPE cells and causes the release of a cell-damaging substance called reactive oxygen species (ROS).
The ROS are thought to be the root cause of subsequent sight loss.
In the RPE cells, especially, the energy [ATP] that is generated by the mitochondria is critical to the eye's function. The retinal cells are multi-functional and need lots of energy,
said Datta. Ideally, we want to restore the mitophagy process and stop the EMT, which leads to irreversible cell damage.
Identifying a novel therapy
Datta's team also identified a new therapeutic approach that may eventually stop and reverse some of the hitherto untreatable damage caused by AMD.
Our work helped us to better understand the molecular mechanics and that allowed us to identify the pathways by which AMD progresses. If we can interrupt those pathways, we can interrupt the disease progression,
he said.
Datta described a treatment approach that shows a lot of promise. It focuses on the removal of ROS by injecting a specially tagged molecule into the RPE cells. This molecule transports a therapeutic drug, N-acetyl cystine (NAC) to the damaged mitochondria, where it scavenges
the harmful ROS from the cell.
Our work has implications that go well beyond that. We see a very real potential to widen our horizon of understanding of cancer pathophysiology, as well. We were also able to develop a nanoparticle-based therapy that is able to prevent cell change - thus providing a potential therapeutic target for many other diseases, like cancer.