Researchers at Indiana University School of Medicine have made a significant discovery regarding the treatment of glaucoma, a neurodegenerative disease that results in vision loss and blindness due to optic nerve damage.
In the United States, over 200,000 individuals are affected by glaucoma annually, but there is no existing treatment. According to a recently published article in Communications Biology, the researchers have identified a new therapeutic target that could enhance the efficacy of glaucoma treatment.
The study discovered that neurons rely on mitochondria for a continuous energy supply, and by restoring mitochondrial homeostasis in damaged neurons, the optic nerve cells can be prevented from harm.
"Age-related neurodegenerative disease, which includes glaucoma, Parkinson's disease, and amyotrophic lateral sclerosis (ALS), is the biggest global health problem. The fundamental mechanisms that we discovered can be used to protect neurons in glaucoma and be tested for the other diseases. We have identified a critical step of complex mitochondrial homeostasis process, which rejuvenates the dying neuron, similar to giving a lifeline to a dying person," said Arupratan Das, Ph.D., assistant professor of ophthalmology and principal investigator of the study.
The Department of Ophthalmology's research team, headed by Michelle Surma and Kavitha Anbarasu, used induced pluripotent stem cells (iPSCs) obtained from both glaucoma patients and non-glaucoma patients, in addition to clustered regularly interspaced short palindromic repeats (CRISPR) engineered human embryonic stem cells, which had been modified with the glaucoma mutation.
The researchers employed stem cell differentiated retinal ganglion cells (hRGCs) obtained from the optic nerve, electron microscopy, and metabolic analysis to identify that retinal ganglion cells suffering from glaucoma experience mitochondrial deficiency, resulting in a greater metabolic burden on each mitochondrion. Consequently, the mitochondria experience damage and degeneration. Mitochondria, which are tube-like structures within cells, are responsible for generating adenosine triphosphate, the cell's primary energy source.
Nevertheless, the research team demonstrated that the process could be reversed by utilizing a pharmacological agent to improve mitochondrial biogenesis. The team also found that retinal ganglion cells have a high capacity for breaking down dysfunctional mitochondria while simultaneously generating new ones to maintain cellular homeostasis.
"Finding that retinal ganglion cells with glaucoma produce more adenosine triphosphate even with less mitochondria was astonishing," Das said. "However, when triggered to produce more mitochondria, the adenosine triphosphate production load was distributed among more mitochondrion which restored the organelle physiology. It is similar to a situation where a heavy stone is carried by fewer people versus a greater number of people—each person will have less pain and injury, just like each mitochondrion will have less difficulty and damage."
In the future, Das intends to examine whether these mechanisms can safeguard the optic nerve in animal models following injury before progressing to human trials, with the aim of developing novel clinical interventions.
Reference: Michelle Surma et al, Enhanced mitochondrial biogenesis promotes neuroprotection in human pluripotent stem cell derived retinal ganglion cells, Communications Biology (2023). DOI: 10.1038/s42003-023-04576-w