Researchers at Indiana University School of Medicine have identified a new therapeutic target that might lead to more effective treatment for glaucoma.
Glaucoma is a neurodegenerative disease that causes vision loss and blindness due to damaged optic nerve. More than 200,000 people are affected by glaucoma in the United States each year. Unfortunately, there is currently no treatment. In an article recently published in Communications Biologyresearchers have found that neurons use mitochondria as a stable source of energy and that restoring mitochondrial homeostasis in diseased neurons can protect optic nerve cells from damage.
“Age-related neurodegenerative disease, which includes glaucoma, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS), is the greatest global health problem,” said Arupratan Das, PhD, assistant professor of ophthalmology and principal investigator of the study. “The fundamental mechanisms we have discovered can be used to protect neurons in glaucoma and be tested for other diseases. We have identified a critical step in the complex process of mitochondrial homeostasis, which rejuvenates the dying neuron, similar to giving a dying person a lifeline. .”
The research team, led by Michelle Surma and Kavitha Anbarasu from the Department of Ophthalmology, used induced pluripotent stem cells (iPSCs) from patients with and without glaucoma as well as pooled regularly spaced short palindromic repeats (CRISPR) of the cells. human embryonic strains with glaucoma mutation. Using stem cell-differentiated retinal ganglion cells (hRGCs) from the optic nerve, electron microscopy, and metabolic analysis, researchers identified glaucomatous retinal ganglion cells with mitochondrial deficiency with metabolic burden larger on each mitochondrion. This leads to mitochondrial damage and degeneration. Mitochondria are tube-like structures in cells that produce adenosine triphosphate, the cell’s energy source.
However, the process might be reversed by enhancing mitochondrial biogenesis by a pharmacological agent. The team showed that retinal ganglion cells are very good at breaking down bad mitochondria, but at the same time produce more of them to maintain homeostasis.
“Finding that retinal ganglion cells with glaucoma produce more adenosine triphosphate even with fewer mitochondria was amazing,” Das said. “However, when triggered to produce more mitochondria, the load of ATP production was distributed among more mitochondria, which restored the physiology of the organelle. This is similar to a situation where a heavy stone is carried by fewer people compared to more people – each person will have less pain and injury, just as each mitochondria will have less difficulty and damage.”
In the future, Das would like to test whether these mechanisms protect the optic nerve in injured animal models before testing them in humans to hopefully lead to new clinical interventions.
