Summary: Restoring mitochondrial homeostasis in diseased neurons can protect the optic nerve from damage and potentially reverse glaucoma symptoms.
Source: Indiana University
Researchers at Indiana University School of Medicine have identified a new therapeutic target that could 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, Ph.D., 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 could 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 ATP 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 organelle physiology. 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.
About this visual neuroscience research news
Author: Press office
Source: Indiana University
Contact: Press Office – Indiana University
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Original research: Free access.
“Enhanced mitochondrial biogenesis promotes neuroprotection in retinal ganglion cells derived from human pluripotent stem cells” by Michelle Surma et al. Communications Biology
Enhanced mitochondrial biogenesis promotes neuroprotection in retinal ganglion cells derived from human pluripotent stem cells
Mitochondrial dysfunctions are widely afflicted in central nervous system (CNS) disorders with minimal understanding on how to improve mitochondrial homeostasis to promote neuroprotection.
Here, we used human stem cell-differentiated retinal ganglion cells (hRGCs) from the CNS, which are highly susceptible to mitochondrial dysfunction due to their unique structure and function, to identify mechanisms for improving quality control. mitochondrial (MQC).
We show that hRGCs are effective in maintaining mitochondrial homeostasis through rapid degradation and biogenesis of mitochondria in acute damage.
Use of a glaucomatous optineurin mutant (E50K) stem cell line, we show that at basal level, mutant hRGCs possess less mitochondrial mass and suffer from mitochondrial swelling due to an excessive load of ATP production.
Activation of mitochondrial biogenesis by pharmacological inhibition of Tank binding kinase 1 (TBK1) restores energy homeostasis, alleviates mitochondrial swelling with neuroprotection against acute mitochondrial damage for glaucomatous patients E50K hRGCs, revealing a new mechanism of neuroprotection.