Age-related neurodegenerative diseases, which include Parkinson's disease and amyotrophic lateral sclerosis in addition to glaucoma, are a significant global health problem. More than 200,000 people in the U.S. are affected annually by glaucoma, which is caused by damaged optic nerves, leading to vision loss and blindness for which there is currently no cure.

The team used induced pluripotent stem cells (iPSCs) from patients with and without glaucoma, as well as clustered regularly interspaced short palindromic repeats (CRISPR) engineered human embryonic stem cells with glaucoma mutations. Electron microscopy and metabolic analysis enabled them to examine mitochondria -- structures within cells that produce adenosine triphosphate, an organic compound that provides the energy needed to drive many cell processes, including muscle contractions and nerve impulses.

The researchers found that the glaucomatous stem cell-differentiated retinal ganglion cells (hRGCs) of the optic nerve suffered from mitochondrial deficiency, which placed more metabolic burden upon each individual mitochondrion, leading to further mitochondrial damage and degeneration. However, they also found that this process could be reversed by enhancing mitochondrial biogenesis via a pharmacological agent.

The team concluded that while retinal ganglion cells are highly efficient in degrading bad mitochondria, they also can produce more mitochondria to maintain homeostasis. In the future, the researchers would like to investigate whether these mechanisms protect injured optic nerves in animals before testing in humans, which they hope will eventually lead to new clinical interventions.

"Finding that retinal ganglion cells with glaucoma produce more adenosine triphosphate even with less mitochondria was astonishing," Arupratan Das, PhD, Indiana University assistant professor of ophthalmology and the principal investigator, said in a statement. "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. 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."

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